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Sperm Sensory Signaling

Dagmar Wachten,1 Jan F. Jikeli,1 and U. Benjamin Kaupp2

1Minerva Max Planck Research Group, Molecular Physiology, Center of Advanced European Studies and Research (caesar), 53175 Bonn, Germany 2Department Molecular Sensory Systems, Center of Advanced European Studies and Research (caesar), 53175 Bonn, Germany Correspondence: [email protected]; [email protected]

Fertilization is exceptionally complex and, depending on the species, happens in entirely different environments. External fertilizers in aquatic habitats, like marine invertebrates or fish, release their gametes into the seawater or freshwater, whereas sperm from most internal fertilizers like mammals cross the female genital tract to make their way to the egg. Various chemical and physical cues guide sperm to the egg. Quite generally, these cues enable signaling pathways that ultimately evoke a cellular Ca2þ response that modulates the wave- form of the flagellar beat and, hence, the swimming path. To cope with the panoply of challenges to reach and fertilize the egg, sperm from different species have developed their own unique repertoire of signaling molecules and mechanisms. Here, we review the differences and commonalities for sperm sensory signaling in marine invertebrates (sea urchin), fish (zebrafish), and mammals (mouse, human).

perm carry a motile hair-like protrusion— species swim on helical paths or chiral ribbons Scalled flagellum—that extends from the (Crenshaw 1990, 1993a,b; Crenshaw and Edel- head. The flagellum serves both as sensory an- stein-Keshet 1993; Corkidi et al. 2008; Su et al. tenna and propelling motor. Sperm flagella and 2012; Jikeli et al. 2015). motile cilia share a similar 9 þ 2 axoneme struc- Various chemical and physical cues guide ture. The sperm cell is propelled by bending sperm to the egg. Quite generally, these cues waves traveling down the flagellum. For steering, enable signaling pathways that ultimately evoke sperm modulate the asymmetry of the flagellar a cellular Ca2þ response that in turn modulates waveform. Sperm motility has been mostlystud- the waveform of the flagellar beat and hence the ied in two dimensions (2D) at the glass/water swimming path (Bo¨hmer et al. 2005; Woodet al. interfaceofshallowobservation chambers (Bo¨h- 2005; Shiba et al. 2008). Four different mecha- mer et al. 2005; Alvarez et al. 2012). When the nisms have been identified that guide sperm to flagellum beats symmetrical with respect to the the egg: chemotaxis, haptotaxis, thermotaxis, long axis of the ellipsoid-shaped head, sperm and rheotaxis (Box 1). move on a straight path; when the flagellum Chemotaxis has been firmly established in beats more asymmetrical, the swimming path marine invertebrates, notably in sperm from the is curved. If unrestricted, sperm from several sea urchin Arbacia punctulata (Fig. 1A). The

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BOX 1

Chemotaxis refers to directed movement of cells in a gradient of a chemical substance. When sperm probe a chemical gradient along a circular or helical path, the spatial gradient is translated into a temporal stimulus pattern, which elicits periodic steering responses. This stimulus pattern is com- posed of a fast periodic component, which results from the helical or circular swimming path, and a mean stimulus component that increases or decreases when swimming up or down the gradient, respectively. During 3D navigation, the torsion of the helical 3D path is in phase (w ¼ 0˚) and the path curvature is in antiphase (w ¼ 180˚) with respect to the fast periodic stimulus component; the helix continuously bends to align with the attractant gradient (“on response”). If sperm happen to swim down the gradient, the mean stimulus level decreases and sperm respond with a strong correcting turn toward higher attractant concentrations (“off response”) (Jikeli et al. 2015). Rheotaxis refers to the directed movement of cells against a fluid flow. It is a mechanical sense because cells register a gradient of flow velocities. Because freely swimming sperm rotate around the longitudinal axis of the flagellum, mouse sperm are exposed to different flow velocities along their length. Haptotaxis refers to the directed movement of cells on a surface that is covered with tethered chemoattractant molecules that form a chemical density gradient. Haptotaxis could occur on the surface of fish eggs and the epithelial layer of the fallopian tube. Thermotaxis refers to directed movement in a temperature gradient. In one concept, sperm “tumble” by hyperactivation followed by straighter and faster swimming periods up the temperature gradient, similar to the tumble-and-run mechanism of bacteria during chemotaxis.

corresponding chemoattractant and the se- egg coat—the micropyle—that provides access quence of signaling events have been identified. to the egg membrane for fusion (Fig. 1B) (Ya- The signaling pathway endows Arbacia sperm nagimachi et al. 2013). Sperm reach the micro- with exquisite sensitivity: they can register pyle probably by haptic interactions with teth- binding of a single chemoattractant molecule ered molecules that line the egg surface and the and transduce this event into a cellular Ca2þ opening or interior of the micropyle. Thus, fish response. Moreover, the navigation strategy in sperm motility might be governed by specific 2D and 3D chemoattractant gradients has been hydrodynamic and haptic interactions with deciphered (Bo¨hmer et al. 2005; Alvarez et al. the egg surface and the micropyle. 2012; Jikeli et al. 2015). In a 2D gradient, sperm In mammals, chemotaxis, rheotaxis, and swim on looping trajectories; in a 3D gradient, thermotaxis have been proposed as guiding the swimming helix bends to align with the gra- mechanisms (Bretherton and Rothschild 1961; dient (Jikeli et al. 2015). Bahat et al. 2003, 2012; Eisenbach and Giojalas Sperm of teleost fish are not actively attract- 2006; Miki and Clapham 2013; Kantsler et ed to the egg from afar (Yanagimachi et al. al. 2014; Boryshpolets et al. 2015; Bukatin 2013). Instead, male fish deposit sperm directly et al. 2015; Perez-Cerezales et al. 2015; Zhang onto the egg surface. Hydrodynamic interac- et al. 2016). Neither one of these mechanisms tions provide a theoretical framework that ex- nor their respective contribution to sperm plains why sperm accumulate at interfaces guidance across the long and narrow oviduct (Rothschild 1963; Winet et al. 1984; Cosson is well understood (Fig. 1C). This ignorance is et al. 2003), follow boundaries in microchan- a result of the technical difficulties to emulate nels, or for that matter stay at the egg surface the complex native conditions encountered by (Elgeti and Gompper 2009; Lauga and Powers mammalian sperm during fertilization. On 2009; Elgeti et al. 2010; Denissenko et al. 2012). their journey to the egg, mammalian sperm un- For fertilization, fish sperm must search for the dergo two processes—capacitation and hyper- narrow entrance to a cone-shaped funnel in the activation—necessary to acquire the potential

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Sperm Sensory Signaling

A B

Jelly egg coat Micropyle

Acrosomal process Chemoattractant

C Uterus

Oviduct

Oocyte

Ovary

Cumulus cells Cervix

Vagina

Sperm

Zona pellucida

Figure 1. Fertilization in marine invertebrates, fish, and mammals. (A) In many marine invertebrates, sperm are attracted by chemotaxis (blue gradient); sperm can elicit the acrosomal process and fertilize the egg at any site of the egg surface. (B) Fish sperm are probably not attracted from afar by chemoattractants. Instead, sperm navigate on the egg surface to a small opening, the micropyle. The mechanisms and molecules underlying directed movement on the egg surface are not known. (C) Mammalian sperm are guided by several mechanisms across the female genital tract. The specifics and underlying molecules are discussed.

to fertilize the egg (Suarez et al. 1993; Suarez reproductive tract and interact with the ciliated 2008). At any given time, only a small fraction epithelial layer that lines the oviduct. Notwith- of sperm is capacitated or hyperactive; there- standing this complexity, major advances have fore, mammalian sperm populations are het- been achieved identifying the signaling mole- erogeneous. Moreover, mammalian sperm are cules and delineating the signaling events that spatially constrained in the convoluted female encode Ca2þ responses.

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D. Wachten et al.

In this review, we discuss what is known increase of cGMP that evokes a Ca2þ response about signaling pathways that control sperm (Matsumoto et al. 2003). Arbacia and Stron- sensory signaling in sea urchin, zebrafish, and gylocentrotus diverged 200 million years ago, in mammals. whereas the split between asteroids (seastars) and echinoids (sea urchins) occurred approxi- SIGNALING IN SEA URCHIN SPERM mately 500 million years ago. Thus, the cGMP- AND OTHER MARINE INVERTEBRATES signaling pathway has been conserved for at least 500 million years in many marine invertebrates Overview across several phyla. In the following, the signal- Oocytes from the sea urchin A. punctulata re- ing components are discussed in more detail. lease a short, species-specific chemoattractant peptide (resact, 14 amino acids in length). The THE CHEMORECEPTOR GUANYLATE chemoattractant binds to a receptor guanylate CYCLASE cyclase (GC) and thereby stimulates the synthe- sis of cGMP (Fig. 2A). In turn, cGMP opens The chemoreceptor GC is composed of three Kþ-selective cyclic nucleotide-gated (CNGK) functional domains (Potter 2011): an extracel- channels. The ensuing hyperpolarization—the lular domain binds the chemoattractant peptide resting potential Vrest is 250 mV—activates resact, an intracellular catalytic domain synthe- two other signaling components: a voltage-gat- sizes cGMP, and a single transmembrane do- ed sodium/proton exchanger (sNHE) and a main connects the binding and catalytic domain hyperpolarization-activated, cyclic nucleotide- and relays the binding event to the cell interior gated (HCN) channel. sNHE activity causes a (Fig. 2A). The oligomeric structure of the GC is small intracellular alkalization that shifts the not known. Mammalian orthologs exist either voltage dependence of the sperm-specific Ca2þ as dimers or trimers (Wilson and Chinkers channel (CatSper, cation channel of sperm) to 1995; Yu et al. 1999; Vaandrager 2002; Ogawa more negative values and thereby “primes” et al. 2004). The overall chemotactic sensitivity CatSper to open during the return of Vm to rest- relies on a high efficacy to capture the chemo- ing value. This return is initiated by the HCN attractant; the efficacy is maximal if every mol- channel that carries an Naþ inward current. Re- ecule that hits the flagellum binds to a receptor covery from the Ca2þ response is accomplished and activates it. The receptor density and affin- by a sodium/calcium/potassium exchanger ity determine the capture efficacy. The flagellum (NCKX) and a plasma membrane Ca2þ-ATPase harbors about 300,000 GC copies at a density of (PMCA) that restore Ca2þ levels, and a phos- 9500 GC molecules/mm2 (Pichlo et al. 2014). In phodiesterase (PDE) that breaks down cGMP. fact, the GC rivals with rhodopsin in photo- How common is this chemotactic signaling receptors (26,000–45,000 rhodopsin mole- pathway? Sperm of the sea urchin Strongylocen- cules/mm2) as one of the most densely packed trotus purpuratus harbor a similar cGMP-sig- membrane receptors (Fotiadis et al. 2003; Gun- naling pathway; however, in shallow recording kel et al. 2015). At very low receptor occupancy, chambers frequently used for the study of che- the binding affinity of the GC is in the picomo- motactic behavior under the microscope, lar range (K1/2 ¼ 90 pM). Thus, high capture S. purpuratus sperm do not display chemotaxis efficacy is achieved by combining an extraordi- (Guerrero et al. 2010). Presumably, the geomet- nary high GC density and ligand affinity. At ric conditions under which 2D chemotaxis higher occupancy, the GC affinity is lower can be observed are severely restricted for (K1/2 ¼ 0.65 nM). In fact, chemoattractant S. purpuratus sperm. Sperm of the sea star Aste- binding spans six orders of magnitude; the rias amurensis also use a peptide as chemoat- broad operational range might involve negative tractant, a GC as chemoreceptor (Nishigaki cooperation among GC subunits, a negative cel- et al. 1996; Matsumoto et al. 2003), and binding lular feedback, or a combination of both. The of the chemoattractant elicits a rapid transient affinity adjustment ensures that, at high chemo-

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Sperm Sensory Signaling

A Sea urchin Resact Na+ Na+ Ca2+ Na+ Ca2+

GC Out Hyper- De- polarization + polarization

NCKX HCN CNGK sNHE PMCA In CatSper SACY

cAMP K+ H+ K+ ATP ADP Ca2+ Ca2+ Ca2+ Δ pHi GTP cGMP GMP

PDE B

155 nm

Figure 2. Signaling pathway in sea urchin sperm. (A) The guanylate cyclase (GC) serves as the receptor for the chemoattractant resact. Resact binding activates the GC, resulting in cGMP synthesis. cGMP activates the Kþ- selective cyclic nucleotide-gated channel (CNGK). Opening of CNGK hyperpolarizes the cell and activates a hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel and a sperm-specific voltage-depen- dent Naþ/Hþ exchanger (sNHE). Opening of HCN channels restores the resting potential, whereas activation of sNHE increases the intracellular pH. Both events activate the principal Ca2þ channel CatSper, leading to a Ca2þ influx. The Ca2þ levels are restored by Ca2þ extrusion through a Naþ/Ca2þ/Kþ exchanger (NCKX) and a Ca2þ ATPase PMCA, whereas cGMP is hydrolyzed by a phosphodiesterase (PDE). On resact binding, sea urchin sperm not only synthesize cGMP,but also cAMP,probably through activation of the soluble adenylate cyclase (SACY), which, at least in mouse sperm, forms a complex with sNHE. One known target for cAMP is the HCN channel, whose voltage-dependent opening is modulated by cAMP. (B) Schematic distribution of GC receptors and CNGK channel on the flagellum. The GC (gray) and CNGK (green) densities are drawn to scale (ratio GC dimer/CNGK is 10:1). The cGMP gradient is depicted in shades of magenta.

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D. Wachten et al.

attractant concentrations prevailing near the developed a noncooperative mechanism of ac- egg, vacant receptors are still available. tivation that is different from the activation of The turnover number of active GC (GC)is CNG channels in photoreceptors and olfactory 72 cGMP molecules/GC/second (Pichlo et al. neurons that require the cooperative binding of 2014). GC activity ceases within 150 ms prob- several ligands (Biskup et al. 2007) and that ably by autodephosphorylation: at rest, six con- operate in the micromolar rather than the served serine residues carry phosphate groups nanomolar range of cAMP or cGMP concentra- that are removed on chemoattractant binding tions (Kaupp and Seifert 2002). (Pichlo et al. 2014). GC inactivation by multi- stage autodephosphorylation might allow for A SPERM-SPECIFIC SODIUM/PROTON precise lifetime control, which could produce EXCHANGER (sNHE) uniform Ca2þ responses and thereby reduce Perhaps one of the most enigmatic signaling “molecule noise,” which limits the precision of events is a sodium/proton exchange. As little gradient sensing. A precedent for such a mech- as we know, in sea urchin sperm, exchange of anism is the visual pigment rhodopsin: stepwise Naþ against Hþ is electroneutral and its activity inactivation by two phosphorylation reactions is controlled by voltage (Lee 1984a,b, 1985; Lee and “capping” of phosphorylated rhodopsin by and Garbers 1986). The exchange is thought arrestin, a stop protein, has been proposed to to be catalyzed by members of a sperm-specific control its lifetime and thereby reduce photon subfamily of solute carriers (SLC9C1 or sNHE) noise (Whitlock and Lamb 1999; Mendez et al. that are structurally unique. They share with 2000; Doan et al. 2006). However, uniform sin- other NHEs a membrane-spanning exchange gle-photon responses also involve other mech- domain that features at least 12 transmembrane anisms (Bisegna et al. 2008; Caruso et al. 2011; segments (Wang et al. 2003). Unlike any other Gross et al. 2012a,b). SLC family members, sNHE harbors a voltage- sensor domain (VSD) similar to voltage-gated THE CYCLIC NUCLEOTIDE-GATED Kþ-, Naþ-, and Ca2þ channels. Moreover, Kþ CHANNEL sNHE carry a CNBD similar to those in CNG and HCN channels. The presence of a VSD and The first electrical event in sea urchin sperm is a CNBD domain is both intriguing and pre- a chemoattractant-induced hyperpolarization sumably meaningful. However, sNHE mole- mediated by a cyclic nucleotide-gated Kþ chan- cules have not been functionally expressed. nel (CNGK). The CNGK is unique compared Therefore, the functions of these domains are with classic CNG channels (Bo¨nigk et al. 2009; unknown, even more so as some channels that Cukkemane et al. 2011). Like voltage-activated harbor a VSD are not gated by voltage (e.g., Ca and Na channels, the large pore-forming v v CNG channels) and some CNG channels are polypeptide consists of four homologous re- not gated by cyclic nucleotides (Brelidze et al. peats; each repeat carries the prototypical 2013; Carlson et al. 2013; Haitin et al. 2013; GYGD pore motif of Kþ channels and a cyclic Fechner et al. 2015). Considering the exquisite nucleotide-binding domain (CNBD). The pH sensitivity of several signaling molecules, CNGK channel can respond to small changes pH homeostasis by sodium/proton exchange in cGMP, because it is exquisitely sensitive to i is an important research area for future work. cGMP (K1/2 ¼ 20 nM) and is activated in a noncooperative fashion. Disabling each of the four CNBDs through mutagenesis revealed that HCN CHANNEL binding of a single cGMP molecule to the third Two HCN channel isoforms, SpHCN1 and repeat is necessary and sufficient to activate the SpHCN2, have been identified in S. purpuratus channel (Bo¨nigk et al. 2009). The other three (Gauss et al. 1998; Galindo et al. 2005). CNBD domains either do not bind cGMP or SpHCN1 (originally called SpIH) (Gauss et al. fail to gate the channel pore. Thus, CNGK has 1998) has been functionally characterized in a

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Sperm Sensory Signaling

mammalian cell line bathed in normal Ringer CNG channel in the outer segment (Vrev ¼ solution. The ionic strength and composition of 0 mV). In sperm, the HCN channel (Vrev ¼ seawater and Ringer solution are entirely differ- 230 mV in Ringer solution) and the CNGK þ ent. Moreover, whether the two orthologs form channel (Vrev ¼ 290 mV) or another K chan- heteromers is not known. Thus, the physiolog- nel could set Vrest at 250 mV (Fig. 3). In fact, ical properties of the native HCN channel might a fraction of SpHCN1 channels is constitutively be distinctively different from those of heterol- open at rest (Gauss et al. 1998). ogously expressed SpHCN1. Notwithstanding, Second, HCN channels carry an inward Naþ SpHCN1 shares several basic properties with current and thus counter the hyperpolarization. mammalian HCN channels in neurons and In retinal rods, HCN channels also repolarize the heart. HCN channels become activated the cell quickly in bright light and prevent Vm þ when the membrane is hyperpolarized (i.e., at from reaching the K equilibrium potential EK. Vm more negative than 0 mV); their activity HCN channels in sperm are likely to serve a is enhanced by cAMP; and their permeability is similar function: they initiate the rapid recovery three- to fourfold larger for Kþ than for Naþ from stimulation and allow sperm to encode a ions. Therefore, under physiological conditions wide range of chemoattractant concentrations. þ þ (Vm .230 mV; high Na outside, high K Third, sperm HCN channels are set apart inside), HCN channels carry a depolarizing in- from their mammalian cousins by two unique ward Naþ current. properties. SpHCN1, after a hyperpolarizing HCN channels may serve multiple func- voltage step, first activates and then inactivates. tions in sea urchin sperm. First, they probably cAMP removes the inactivation and conse- contribute to the unusually low Vrest together quently enhances the open probability Po (Fig. with another ion channel with different ion se- 3). In contrast, mammalian HCN channels do lectivity (Fig. 3). There is a precedent in rod not inactivate and cAMP shifts the Po2Vm re- photoreceptors, which hyperpolarize on light lation to less negative potentials without affect- stimulation. Two channels set Vrest (240 mV): ing much the maximal current. Because of the þ aK channel in the inner segment (reversal exquisite cAMP sensitivity (K1/2 ¼ 0.75 mM) potential Vrev ¼ 275 mV) and a nonselective and the large effect of cAMP on Po, modulation of sperm HCN channels by cAMP might con- trol the sensitivity of sperm, that is, contribute 1.0 to adaptation. Finally, HCN channels are often referred to as pacemakers, because they control rhythmic 0.5 electrical activity in neurons and cardiac myo- cytes. HCN channels may serve a similar func-

Open probability tion in sperm. The periodic swimming path temporally organizes the stimulus pattern that is perceived by sperm. The ensuing periodic –100 –80 –60 –40 –20 0 stimulation pattern entrains Ca2þ oscillations Vm (mV) (Bo¨hmer et al. 2005). Future studies need to Figure 3. Membrane potential. The resting potential examine whether HCN channels are important 2þ Vrest of 250 mV (green arrowhead) is probably for pacing Ca oscillations in sperm. determined by the hyperpolarization and cyclic nu- cleotide-gated (HCN) channels (Vrev 230 mV in Ringer solution, orange arrowhead) and the Kþ-se- CatSper CHANNEL lective cyclic nucleotide-gated (CNGK) channel (V rev CatSper is one of the most complex voltage- 920 mV, black arrowhead). The V1/2 of HCN opening is similar with and without cAMP, whereas gated ion channels. Like in mammalian sperm, open probability Po is much larger in the presence of the CatSper channel in A. punctulata comprises cAMP (red) than without (blue). four homologous a subunits (CatSper 1–4)

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D. Wachten et al.

and at least three auxiliary subunits: CatSper b, cules that reestablish resting pHi are not known. CatSper g, and CatSper d (Seifert et al. 2015). At Ca2þ levels return to baseline owing to the rest, CatSper is closed and is activated by a activity of a sodium/calcium/potassium ex- “switch-like” mechanism that involves two changer (NCKX) (Su and Vacquier 2002), and steps. The alkalization by sNHE shifts the volt- aCa2þ-ATPase in the plasma membrane age dependence to more negative values; the pH (PMCA) (Gunaratne et al. 2006). How these dependence of this cooperative shift is ex- molecules are regulated is not known (Fig. 2A). ceptionally steep (Hill coefficient of about 11) (Seifert et al. 2015). During recovery from hy- SINGLE-MOLECULE SENSITIVITY BY THE perpolarization, CatSper opens (Fig. 2A). The NUMBERS high cooperativity permits CatSper to trans- duce the minute elementary changes in pHi Several mechanisms have been proposed that 2þ and Vm into a Ca response. explain ultrasensitivity in cells. These concepts largely originate from the study of signaling in photoreceptors, olfactory neurons, and bacte- ADENYLATE CYCLASE AND cAMP—IN ria. Mechanisms include (1) lattices of highly SEARCH OF A FUNCTION cooperative chemoreceptors in bacteria (Mad- In contrast to cGMP,much less is known about dock and Shapiro 1993; Bray et al. 1998; Duke the regulation and function of cAMP. Stimula- and Bray 1999; Gestwicki and Kiessling 2002; tion with resact evokes a rise of cAMP that is Sourjik and Berg 2004); (2) high multistage delayed with respect to the increase of cGMP gain provided by a cascade of enzymatic reac- (Kaupp et al. 2003). The synthesis of cAMP,pre- tions in photoreceptors (Pugh and Lamb 2000; sumably by a soluble adenylate cyclase (SACY) Yau and Hardie 2009; Kaupp 2010); (3) local (Nomura et al. 2005), is enhanced under hyper- signaling by supramolecular complexes (trans- polarizing conditions (Beltra´n et al. 1996) and ducisome or signalosome) (Huber et al. 1996; alkaline pHi (Cook and Babcock 1993), but is Tsunoda et al. 1997; Scott and Zuker 1998); and insensitive to Ca2þ (Nomura et al. 2005). Each (4) restricted diffusion of chemical messengers of these properties is at odds with those of other in confined cellular subcompartments (Rich SACYs, which are activated by bicarbonate and et al. 2000, 2001). Ca2þ (Chen et al. 2000; Jaiswal and Conti 2003; As will become clear, sperm use different Steegborn et al. 2005; Kleinboelting et al. 2014). mechanisms to achieve single-molecule sensi- Either the SACY in sperm of sea urchin mam- tivity. First, sperm do not rely on arrays of mals are entirely different, or a different mem- receptor clusters that display positive coopera- brane-spanning AC is involved in sea urchins. tivity, although the GC may adopt a supramo- Protein kinase A (PKA) in mammalian sperm lecular organization that, however, serves other represents a sperm-specific isoform that is dif- functions. ferent from that in somatic cells (Nolan et al. Second, amplification at the receptor level 2004; Burton and McKnight 2007). is orders of magnitude lower in sperm com- pared with rod photoreceptors. Rods also enter- tain a cGMP-signaling pathway that endows MOLECULES FOR RECOVERY these cells with single-photon sensitivity. Cap- Although the signaling events that excite sea ture of a photon initiates the hydrolysis of 2000 urchin sperm have been delineated in great de- to 72,000 cGMP molecules, depending on the tail, much less is known about recovery and species, by two-stage amplification (Pugh and adaptation. For recovery from chemoattractant Lamb 2000; Burns and Pugh 2010; Arshavsky 2þ stimulation cGMP,cAMP,pHi, [Ca ]i, and Vm and Burns 2014). For sperm, a lower and upper must return to baseline levels. The elevated limit of the number of cGMP molecules in- cGMP level is probably lowered by a cGMP-spe- volved in single-molecule events has been esti- cific PDE 5 (Su and Vacquier 2006). The mole- mated by two different methods. During its life-

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Sperm Sensory Signaling

time, a GC synthesizes 11 cGMP molecules gellar diameter and, within 100 ms, it equili- (Pichlo et al. 2014). Using fluorescent caged brates along the length of the flagellum. In a cGMP,the number of cGMP molecules required 155-nm-long segment of the flagellum, neglect- for a single-molecule response was estimated to ing cGMP binding to high-affinity buffers be about 47 cGMP molecules (Bo¨nigk et al. or hydrolysis by PDEs, the cGMP transiently 2009). Both estimates are fraught with uncer- increases to micromolar concentrations that tainties. The turnover rate of cGMP synthesis saturate any nearby CNGK channels (K1/2 ¼ was determined at relatively high chemoat- 26 nM) (Bo¨nigk et al. 2009). For a regular ar- tractant concentrations and has been linearly rangement of 100 GC dimers in a 155 155- extrapolated to the single-molecule regime. nm membrane patch, an active GC would However, the catalytic turnover might depend be girded by nine CNGK channels at a dis- on the occupation level of the GC. For example, tance not farther than 100 nm (Fig. 2B); these if the GC exists as a dimer and if each subunit next neighbors would be first served with cGMP binds a resact molecule (stoichiometry 2:2), the molecules. Finally, the input resistance of sperm turnover of single- or double-occupied recep- (5GV) (Navarro et al. 2007; Zeng et al. 2013) tors might be different. Finally, it is assumed is at least five-fold higher than that of mamma- that the concentration of membrane-permeant lian rod photoreceptors (1–2 GV) (Schneeweis caged cGMP has completely equilibrated across and Schnapf 1995); thus, by changing the open the membrane. Apart from these uncertainties, probability of only a few CNGK channels, cGMP amplification in rods is about 600-fold sperm can produce a single-molecule response. larger than in sperm. Nonetheless, rod and In conclusion, there is no need to invoke sperm operate at a similar level of sensitivity: high amplification, signaling complexes, or re- binding of a molecule to sperm or capture of a stricted diffusion to account for single-molecule photon by rods each evokes a DVm of 1–2 mV sensitivity of sperm. The exquisite cGMP sensi- (Pugh and Lamb 2000; Stru¨nker et al. 2006). tivity of CNGK channels, the minuscule flagel- Taking into account a volume ratio Vrod/ lar volume, and the high input resistance are key. Vflagellum of 80/2fl¼ 40:1, the change in Aword of caution: all of these conclusions have cGMP concentration per unit volume is only been inferred from population measurements. 15 larger in rods compared with sperm. Future work requires to study single-molecule Third, it has been argued that second-mes- sensitivity in single sperm cells. Notwithstand- senger concentrations steeply decay from the ing, the hallmarks of this signaling mechanism site of synthesis (Rich et al. 2000, 2001), which might provide a blueprint for chemical sensing calls either for a signaling complex between re- in small compartments such as olfactory cilia, ceptors and downstream targets or for restricted insect antennae, or even synaptic boutons. diffusion in subcellular compartments channel- ing the messenger to the target. In order for a SIGNALING IN FISH GC–CNGK complex to be effective, receptor (GC) and target (CNGK channel) ought to be Navigation of fish sperm and the underlying present stoichiometrically, whereas, in fact, the signaling pathways must be arguably different GC is 24-fold more abundant than the CNGK from those of marine invertebrates and mam- (Pichlo et al. 2014). Thus, a “transducisome” mals. First, teleost fish lack CatSper channels between GC and CNGK is unlikely to contrib- (Cai and Clapham 2008). However, activation ute to single-molecule sensitivity of the sea ur- of sperm motility requires Ca2þ influx (Billard chin sperm. 1986; Takai and Morisawa 1995; Alavi and Cos- The impact of cGMP diffusion from a point son 2006; Cosson et al. 2008; Morisawa 2008). source at the membrane in a small cylindrical Motility is activated by hyper- or hypoosmotic compartment like the flagellum was assessed shock after spawning of sperm into seawater or (Pichlo et al. 2014). Within 15 ms, the freshwater, respectively (Krasznai et al. 2000; cGMP concentration equilibrates across the fla- Vines et al. 2002; Alavi and Cosson 2006; Cherr

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et al. 2008; Morisawa 2008). Therefore, Ca2þ that are located upstream and downstream of influx in fish sperm involves other Ca2þ chan- CNGK in the signaling pathways in fish. nels or Ca2þ release from intracellular stores. Second, the ionic milieu seriously con- strains ion channel function. Sperm of freshwa- MAMMALIAN SPERM—DIFFERENCES AND COMMONALITIES ter fish, marine invertebrates, and mammals are facing entirely different ionic milieus. Kþ and Mammalian sperm navigate across the female Naþ concentrations in freshwater are extremely genital tract to reach the egg. During this transit, low (70 mM and 200 mM, respectively) com- sperm undergo capacitation and hyperactiva- pared with the orders-of-magnitude higher tion. Capacitation is a complex, ill-defined mat- concentrations in seawater or the oviduct (Alavi uration process. Hyperactivation is initiated and Cosson 2006; Hugentobler et al. 2007). Fur- during capacitation and is characterized by a thermore, [Ca2þ] in seawater is high (10 mM), whip-like beat of the flagellum, which is essen- whereas in freshwater it is low (,1 mM). The tial to penetrate the egg’s vestments—the zona low salt concentrations in freshwater probably pellucida and cumulus cells (Suarez et al. 1993; require ion channels that are differently de- Suarez 2008). signed. In fact, none of the ion channels con- During their journey from the epididymis trolling electrical and Ca2þ signaling of fish via the female genital tract to the egg, sperm sperm had been known until recently. experience an ever-changing environment, in- Unexpectedly, although the principal tar- cluding large differences in pH, ionic milieu, gets of hyperpolarization—the sNHE and viscosity, and epithelial surfaces. To adapt to CatSper—are absent in fish, orthologs of the these changes, mammalian sperm have devel- sperm CNGK channel are present in various oped species-specific signaling mechanisms to fish genomes (Fig. 4) (Fechner et al. 2015). Sur- reach and fertilize the egg. These differences are prisingly, the CNGK channel of zebrafish differs also reflected by large variations in sperm size from its sea urchin cousin: it is activated by and shape. Rodent sperm have a sickle-shaped alkalinization, but not by cyclic nucleotides; head and a fairly long flagellum, whereas pri- moreover, the channel is localized in the head mate sperm feature an oval-shaped head and rather the flagellum; finally, the sea urchin a shorter flagellum (Miller et al. 2015). In the CNGK is blocked by intracellular Naþ, whereas following, differences and commonalities of the blockof the zebrafish CNGK is muchweaker. sensory signaling between mouse and human Future studies need to identify the molecules sperm are described.

Ca2+

Zebrafish

Out ?

Hyperpolarization V Ca CNGK In

K+ [Ca2+]↑ Δ i ? pHi

Motility response

Figure 4. Signaling pathway in zebrafish. Only the Kþ-selective cyclic nucleotide-gated (CNGK) channel has 2þ been identified. The other components, in particular the Ca channel, are not known. A change in pHi that is produced by unknown mechanisms upstream of CNGK causes hyperpolarization and, in turn, Ca2þ influx.

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Sperm Sensory Signaling

CatSper IS KEY FOR Ca2þ SIGNALING Furthermore, these Ca2þ domains also organize the spatiotemporal pattern of sperm capacita- Ca2þ is also key for mammalian sperm naviga- tion (Chung et al. 2014). tion and fertilization: Ca2þ controls the flagellar The CatSper channel is a polymodal sensor beat pattern and, thus, sperm motility, naviga- that registers changes in membrane voltage, 2þ tion, rheotaxis, and hyperactivation. Ca is pHi, and the concentration of various ligands. also required for the acrosome reaction, which Mouse CatSper is less voltage-dependent than is needed to penetrate the egg’s vestments and human CatSper, but shows a higher pH sensi- for capacitation. tivity (Kirichok et al. 2006; Lishko and Kirichok 2þ Many different Ca channels have been 2010; Lishko et al. 2011). At physiological pHi proposed to control sperm function (Darszon (7.4), the V1/2 for human and mouse CatSper is et al. 2011). Although some voltage-dependent þ85 mVand þ11 mV,respectively (Lishko and Cav channels might be present during sperma- Kirichok 2010; Lishko et al. 2011), indicating togenesis, CatSper has been identified as the that at a resting membrane potential of Vrest ¼ principal Ca2þ channel in mature mammalian 230 mV, mouse CatSper would be partially sperm (Fig. 5) (Lishko et al. 2012). CatSper open, whereas the human CatSper would be forms a heteromeric channel complex made mostly closed. up of at least seven different subunits. In human sperm, the female sex hormone Catsper1–4 (a-subunits) form the pore, where- progesterone and prostaglandins in the oviduc- as CatSperb, g,andd represent auxiliary sub- tal fluid activate CatSper and cause a Ca2þ in- units that are associated with the pore-forming flux (Lishko et al. 2011; Stru¨nker et al. 2011; complex (Ren et al. 2001; Carlson et al. 2003; Brenker et al. 2012). Progesterone has been pro- Liu et al. 2007; Qi et al. 2007; Wang et al. 2009; posed to act as a chemoattractant, controlling Chung et al. 2011). Although basal motility is sperm navigation and fertilization (Teves et al. not affected by targeted disruption of CatSper 2006; Oren-Benaroya et al. 2008). The CatSper subunits in mice, hyperactivation is abolished activation occurs almost instantaneously and and capacitation is impaired (Carlson et al. does not involve G-protein-coupled receptors 2003; Quill et al. 2003; Chung et al. 2014). (GPCRs) or G-proteins (Lishko et al. 2011; Finally, rheotaxis is abolished in CatSper null Stru¨nker et al. 2011; Brenker et al. 2012), sug- sperm (Miki and Clapham 2013). Whether gesting that CatSper is gated either directly by other potential navigation strategies like ther- progesterone or a closely associated receptor. motaxis or chemotaxis also rely on CatSper is Recently, the orphan enzyme a/b hydrolase do- not known. However, a double knockout of main-containing protein 2 (ABHD2) has been CatSper and KSper conclusively shows that identified as the progesterone receptor in hu- mouse sperm harbor no voltage and pH-de- man sperm (Fig. 5) (Miller et al. 2016). On pendent ion channels other than CatSper and progesterone binding, ABHD2 cleaves the en- KSper (Zeng et al. 2013). In line with the find- docannabinoids 1- and 2-arachidonoylglycerol ings from mouse sperm, mutations in the hu- (AGs) into free glycerol and arachidonic acid man CatSper result in male infertility (Avidan (Miller et al. 2016). AGs inhibit the CatSper et al. 2003; Zhang et al. 2007; Avenarius et al. current ICatSper; however, hydrolysis of AGs by 2009; Smith et al. 2013; Jaiswal et al. 2014). ABHD2 relieves their inhibition (Miller et al. CatSper serves as a platform along the fla- 2016). Mouse sperm are insensitive to stimula- gellum to create signaling domains. CatSper tion with progesterone. The species specificity channels form a quadrilateral arrangement in of progesterone seems to be based on the differ- three dimensions that organizes structurally ence in lipid homeostasis and localization of distinct Ca2þ signaling domains (Chung et al. ABHD2 (Miller et al. 2016). In mouse sperm, 2014). Loss of any one of the CatSper channel ABHD2 is localized to the acrosome rather than subunits destroys the organization of these sig- the sperm flagellum (in contrast to human naling domains and hyperactivated motility. sperm). Thus, ABHD2 does not colocalize

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Mouse Out Slo3 NCX LRRC52

NHA1 PMCA sNHE In CatSper SACY

+ 2+ 2+ H+ H Ca K+ Ca ATP ADP Ca2+ ? Δ ? pHi onSeptember24,2021-PublishedbyColdSpringHarborLaboratoryPress

B Na+ H+ Ca2+ Na+ Ca2+ Human P Out NCX Hv1 Slo3 LRRC52 ABHD2 PMCA ieti ril as article this Cite CatSper In sNHE SACY H+ H+ Ca2+ ATP ADP ? Ca2+ K+ Ca2+ Δ ? pHi

2þ odSrn abPrpc Biol Perspect Harb Spring Cold Figure 5. Comparison of signaling pathways in mouse and human sperm. (A) Mouse sperm. The principal Ca channel is CatSper. CatSper opening is regulated by changes in intracellular pH (DpHi) and changes in membrane potential. The membrane potential is controlled by the pH-dependent Slo3 Kþ channel. Its auxiliary subunit LRRC52 controls the pH- and voltage-dependent opening of Slo3. The activation of Slo3 during Ca2þ signaling is ill defined. Prominent candidates for controlling the intracellular pH are two Naþ/Hþ exchangers, the sperm-specific sNHE and NHA1. sNHE is localized in a protein complex with the soluble adenylate cyclase (SACY). However, the role of sNHE and NHA1 in controlling the intracellular pH has yet to be confirmed. The recovery of the Ca2þ homeostasis after CatSper opening is not well under- stood. In mouse sperm, the Ca2þ-ATPase PMCA4 extrudes Ca2þ and controls sperm hyperactivation. The role of a Naþ/ Ca2þ exchanger (NCX) has yet to be confirmed. (B) Human sperm. As in mouse sperm, the principal Ca2þ channel is CatSper, which is also regulated by changes in pHi and membrane voltage. Furthermore, CatSper is activated by binding of progesterone (P) to the lipid hydrolase ABHD2, which hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2AG) to 2016;9:a028225 arachidonic acid and glycerol. This relieves CatSper inhibition by 2AG and opens the channel. In human sperm, the þ 2þ principal K channel is also Slo3; it is regulated by Ca and to a lesser extent by changes in pHi. Presumably, Slo3 is 2þ þ placed downstream from CatSper on the recovery branch of Ca signaling. Human sperm contain an H channel (Hv1), þ which carries an outward rectifying H current. Hv1 and sNHE are the candidates to control pHi in human sperm. The recovery of the Ca2þ response is also thought to be regulated my members of the NCX and PMCA family. However, their molecular identity is yet to be confirmed. Pale icons indicate molecules whose identity is yet to be confirmed; dotted lines present signaling pathways with weak experimental evidence; question marks indicate hypothetical signaling pathways that have not yet been confirmed experimentally. Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Sperm Sensory Signaling

with CatSper. In addition, mouse sperm lose ionchannelsinmouse spermthatregulatemem- AGs during their transit through the epididy- brane potential and Ca2þ influx in response to mis; thus, CatSper is no longer inhibited by AGs alkalization (Zeng et al. 2013). and does not require progesterone-dependent In contrast to mouse sperm, the Kþ current hydrolysis of AGs for activation (Miller et al. in human sperm is only weakly pH-dependent, 2016). In contrast, human sperm maintain but strongly regulated by Ca2þ (Brenker et al. high AG levels and require stimulation with 2014). Consequently, the membrane potential progesterone for activation (Miller et al. 2016). in human sperm is sensitive to changes in Ca2þ þ In addition to steroids and prostaglandins, and less so to pHi. Furthermore, the K current other chemicals as diverse as odorants, men- is inhibited by progesterone (Mannowetz et al. thol, and analogs of cyclic nucleotides, as well 2013; Brenker et al. 2014). Efforts to identify the as various endocrine-disrupting chemicals molecules underlying the Kþ channel in human (EDCs), can also activate CatSper (Brenker sperm provided mixed results. Initially, it was et al. 2012; Tavares et al. 2013; Schiffer et al. thought that Slo1, the Ca2þ-regulated member 2014). EDCs are omnipresent in food, house- of the Slo family carries the Kþ current in hu- hold, and personal care products and have been man sperm (Mannowetz et al. 2013). However, linked to decreasing fertility rates in the Western overwhelming evidence now shows that Slo1 is world (Bergman et al. 2013). Whether these absent in human sperm and that a Ca2þ-regu- chemicals activate CatSper via ABHD2 or an- lated Slo3 channel carries Kþ currents (Brenker other mechanism is not known. et al. 2014). In particular, the properties of het- erologously expressed human Slo3 match those of native Kþ currents, including block by quin- Kþ CHANNELS AND THE CONTROL OF THE idine and clofilium, inhibition by progesterone, MEMBRANE POTENTIAL modest pH sensitivity but large Ca2þ-sensitiv- The principal Kþ channel in mouse sperm is ity, and single-channel conductance (70 pS) Slo3, a member of the Slo family of ion channels (Brenker et al. 2014). Thus, human sperm (Schreiberet al. 1998; Santi et al. 2010; Zeng et al. switched the ligand selectivity of Slo3 from 2þ 2011). Deletion of Slo3 severely impairs male pHi to Ca rather than to adopt a new Slo fertility (Santi et al. 2010; Zeng et al. 2011). isoform. Activation of the Ca2þ-sensitive Slo3 The Slo3 channel in mouse sperm is activated might curtail Ca2þ influx via CatSper, suggest- at pHi . 6.0 and membrane potentials .0mV ing that Slo3 in human sperm is placed down- (pH 7); it carries a hyperpolarizing outwardcur- stream of CatSper on the recovery branch of rent (Navarro et al. 2007; Zeng et al. 2011). Apart Ca2þ signaling, whereas in mouse sperm, Slo3 from the pore-forming subunit encoded by the at alkaline pH could hyperpolarize the cell and Slo3 gene, the channel complex also containsthe would open CatSper through a voltage-depen- auxiliary subunits LRRC52 and LRRC26 (leu- dent alkalization. cine-rich repeat-containing proteins). LRRC52 regulates the pH- and voltage-dependent open- Ca2þ CLEARANCE MECHANISMS ing of the channel complex (Yang et al. 2011; Zeng et al. 2015). The development of hyperac- To restore Ca2þ levels, Ca2þ needs to be extrud- tivated motility during capacitation of mouse ed from the cytoplasm or stored in intracellular sperm is dependent on cytosolic alkalization fol- organelles. In mouse sperm, the plasma mem- 2þ 2þ lowed by an increase of [Ca ]i (Suarez 2008). brane Ca -ATPase PMCA4 seems to be impor- Slo3 mediates the hyperpolarization on alkaliza- tant to maintain Ca2þ homeostasis (Okunade tion (Zeng et al. 2011) and recent evidence sug- et al. 2004; Schuh et al. 2004). PMCA4 null male gests that hyperpolarization indirectly activates mice are infertile and are unable to undergo CatSper by promoting a rise of pHi through a hyperactivation. PMCA pumps are the fastest voltage-dependent mechanism (Chavez et al. Ca2þ extrusion mechanisms in sperm. Naþ/ 2014). Together, Slo3 and CatSper are the sole Ca2þ exchanger (NCX) and mitochondrial

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Ca2þ uniporter are slower (Wennemuth et al. er, sNHE is found in a complex with the SACY, 2003a). However, the underlying molecules in the predominant source for cAMP in mamma- mouse sperm are ill defined. In principal, sim- lian sperm (Wang et al. 2007). In fact, the loss of ilar Ca2þ clearance mechanisms also exist in sNHE results in a concomitant loss of SACY. human sperm. Future studies need to investi- Thus, it is difficult to disentangle the physiolog- gate the recovery branch of Ca2þ signaling in ical function of sNHE and the SACY. Cyclic more detail. AMP is essential for sperm development, mo- tility, and maturation in the female genital tract (Visconti et al. 1995; Wennemuth et al. 2003b; REGULATION OF pHi—ENIGMATIC IN Kra¨hling et al. 2013). Mice lacking SACY are MOUSE, BUT NOT SO MUCH IN HUMAN infertile and the sperm are immotile (Esposito SPERM et al. 2004). The motility defect in sNHE-null Changes in pHi control capacitation, hyperacti- mice can be rescued by application of mem- vation, motility, and many signaling molecules brane permeable cAMP analogs or by optoge- are pH-dependent. Several molecules have been netic stimulation of cAMP production (Jansen proposed to control pHi, including the voltage- et al. 2015), showing that the motility defect and gated proton-specific channel Hv1 (Lishko et al. thereby the infertile phenotype is solely due to 2010), different members of the protein family the loss of SACY, but not sNHE (Wang et al. of solute carriers (SLC; sodium–proton ex- 2003). Recently, another NHE, NHA1, has changers and bicarbonate transporters), and been shown to control sperm function (Liu carbonic anhydrases (Nishigaki et al. 2014). et al. 2010; Chen et al. 2016). However, infor- In human sperm, the proton channel Hv1 mation about its role in controlling pHi in carries a large outwardly rectifying Hþ current mouse sperm is missing. Surprisingly, NHA1- (Lishko et al. 2010). The channel features knockout mice also seem to display attenuated unique characteristics: it is activated by mem- cAMP signaling and impaired sperm motility. brane depolarization, regulated by pHi and Future studies need to reveal whether NHA1 pHo, and inhibited by zinc (Ramsey et al. regulates pHi in mouse sperm. 2006; Sasaki et al. 2006). These characteristics may be particularly important during the tran- SPERM COMPARTMENTALIZATION AND sit through the female genital tract. When SUPRAMOLECULAR STRUCTURES sperm are ejaculated, they are mixed with the seminal plasma that contains millimolar con- Mammalian sperm show different levels of centrations of zinc, rendering the channel inac- compartmentalization. The two major com- tive (Lishko and Kirichok 2010). During the partments are the head and the flagellum. The transit through the female genital tract, zinc is flagellum itself is separated into the midpiece, chelated by proteins, suggesting that this causes principal piece, and the endpiece, where signal- a gradual activation of the channel (Lishko and ing molecules and second messenger dynamics Kirichok 2010). Hv1 is also thought be activated are spatially organized. by capacitation (Lishko et al. 2010). However, As described above, the CatSper complex the underlying mechanism is still enigmatic. creates structurally distinct Ca2þ-signaling do- In contrast to human sperm, mouse sperm mains along the principal piece of mouse sperm do not contain an outwardly rectifying Hþ cur- (Chung et al. 2014). In human sperm, CatSper rent and Hv1 null male mice do not show a is also localized in the principal piece, and pro- fertility defect (Miller et al. 2015). How the gesterone stimulation first elicits a Ca2þ in- pHi is regulated in mouse sperm is not known. crease in the principal piece and midpiece, The most likely candidate has been an Naþ/Hþ which then propagates to the head (Servin-Ven- exchanger specific for sperm (sNHE). Indeed, ces et al. 2012). Furthermore, it has been shown mice lacking sNHE are infertile because the that cAMP signaling pathways are compart- sperm are immotile (Wang et al. 2003). Howev- mentalized in the head and flagellum (Wert-

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Sperm Sensory Signaling

heimer et al. 2013) and that cAMP dynamics 2003. CATSPER2, a human autosomal nonsyndromic are also organized in distinct domains along male infertility gene. Eur J Hum Genet 11: 497–502. Bahat A, Tur-Kaspa I, Gakamsky A, Giojalas LC, Breitbart H, the flagellum (Mukherjee et al. 2016). How- Eisenbach M. 2003. Thermotaxis of mammalian sperm ever, the molecular mechanisms underlying cells: A potential navigation mechanism in the female the compartmentalization of cAMP dynamics genital tract. Nat Med 9: 149–150. have not been identified yet. The combination Bahat A, Caplan SR, Eisenbach M. 2012. Thermotaxis of human sperm cells in extraordinarily shallow tempera- of genetically encoded biosensors with optoge- ture gradients over a wide range. PLoS ONE 7: e41915. netics holds great promise to map the dynamics Beltra´n C, Zapata O, Darszon A. 1996. Membrane potential of cAMP signaling in live cells in precise spatio- regulates sea urchin sperm adenylylcyclase. Biochemistry temporal and quantitative terms. 35: 7591–7598. Bergman A, Heindel JJ, Kasten T, Kidd KA, Jobling S, Neira M, Zoeller RT,Becher G, Bjerregaard P,Bornman R, et al. 2013. The impact of endocrine disruption: A consensus OUTLOOK statement on the state of the science. Environ Health Per- spect 121: A104–A106. Although many molecules in the flagellum of Billard R. 1986. Spermatogenesis and spermatology of some mammalian sperm have been identified that are teleost fish species. Reprod Nutr Dev 26: 877–920. 2þ involved in electrical and Ca signaling, we do Bisegna P, Caruso G, Andreucci D, Shen L, Gurevich VV, not know which sensory modality they serve: Hamm HE, DiBenedetto E. 2008. Diffusion of the second messengers in the cytoplasm acts as a variability suppres- rheotaxis, chemotaxis, haptotaxis, or thermo- sor of the single photon response in vertebrate photo- taxis? In fact, other molecules, like rhodopsin, transduction. Biophys J 94: 3363–3383. G-proteins, phospholipase C, TRPC3 channels, Biskup C, Kusch J, Schulz E, Nache V,Schwede F,Lehmann F, and IP -gated channels have been implied in Hagen V, Benndorf K. 2007. Relating ligand binding to 3 activation gating in CNGA2 channels. Nature 446: 440– thermosensation of human sperm (Perez-Cere- 443. zales et al. 2015). Moreover, yet other molecules Bo¨hmer M, Van Q, Weyand I, Hagen V, Beyermann M, have been suggested for chemotaxis of human Matsumoto M, Hoshi M, Hildebrand E, Kaupp UB. 2þ sperm in a progesterone gradient (Teves et al. 2005. Ca spikes in the flagellum control chemotactic behavior of sperm. EMBO J 24: 2741–2752. 2009). Future work is required to unequivocally Bo¨nigk W, Loogen A, Seifert R, Kashikar N, Klemm C, assign signaling pathways to behavioral re- Krause E, Hagen V, Kremmer E, Stru¨nker T, Kaupp UB. sponses during directed movement. 2009. An atypical CNG channel activated by a single cGMP molecule controls sperm chemotaxis. Sci Signal 2: ra68. Boryshpolets S, Perez-Cerezales S, Eisenbach M. 2015. Be- ACKNOWLEDGMENTS havioral mechanism of human sperm in thermotaxis: A role for hyperactivation. Hum Reprod 30: 884–892. We thank Dr. R. Pascal for preparing the figures Bray D, Levin MD, Morton-Firth CJ. 1998. Receptor clus- and H. Krause for preparing the manuscript. tering as a cellular mechanism to control sensitivity. Na- ture 393: 85–88. Brelidze TI, Gianulis EC, DiMaio F, Trudeau MC, Zagotta REFERENCES WN. 2013. Structure of the C-terminal region of an ERG channel and functional implications. Proc Natl Acad Sci Alavi SM, Cosson J. 2006. Sperm motility in fishes. II: Effects 110: 11648–11653. of ions and osmolality: A review. Cell Biol Int 30: 1–14. Brenker C, Goodwin N, Weyand I, Kashikar ND, Naruse M, Alvarez L, Dai L, Friedrich BM, Kashikar ND, Gregor I, Kra¨hling M, Mu¨ller A, Kaupp UB, Stru¨nker T. 2012. The Pascal R, Kaupp UB. 2012. The rate of change in Ca2þ CatSper channel: A polymodal chemosensor in human concentration controls sperm chemotaxis. J Cell Biol 196: sperm. EMBO J 31: 1654–1665. 653–663. Brenker C, Zhou Y, Mu¨ller A, Echeverry FA, Tro¨tschel C, Arshavsky VY, Burns ME. 2014. Current understanding of Poetsch A, Xia XM, Bo¨nigk W, Lingle CJ, Kaupp UB, et signal amplification in phototransduction. Cell Logist 4: al. 2014. The Ca2þ-activated Kþ current of human sperm e29390. is mediated by Slo3. eLife 3: e01438. Avenarius MR, Hildebrand MS, Zhang Y, Meyer NC, Smith Bretherton FP,Rothschild. 1961. Rheotaxis of spermatozoa. LL, Kahrizi K, Najmabadi H, Smith RJ. 2009. Human Proc R Soc Lond B 2 153: 490–502. male infertility caused by mutations in the CATSPER1 Bukatin A, Kukhtevich I, Stoop N, Dunkel J, Kantsler V. channel protein. Am J Hum Genet 84: 505–510. 2015. Bimodal rheotactic behavior reflects flagellar beat Avidan N, Tamary H, Dgany O, Cattan D, Pariente A, Thul- asymmetry in human sperm cells. Proc Natl Acad Sci 112: liez M, Borot N, Moati L, Barthelme A, Shalmon L, et al. 15904–15909.

Cite this article as Cold Spring Harb Perspect Biol 2016;9:a028225 15 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

D. Wachten et al.

Burns ME, Pugh EN Jr. 2010. Lessons from photoreceptors: Crenshaw HC. 1993a. Orientation by helical motion. I: Ki- Turning off G-protein signaling in living cells. Physiology nematics of the helical motion of organisms with up to (Bethesda) 25: 72–84. six degrees of freedom. Bull Math Biol 55: 197–212. Burton KA, McKnight GS. 2007. PKA, germ cells, and fer- Crenshaw HC. 1993b. Orientation by helical motion. III: tility. Physiology (Bethesda) 22: 40–46. Microorganisms can orient to stimuli by changing the Cai X, Clapham DE. 2008. Evolutionary genomics reveals direction of their rotational velocity. Bull Math Biol 55: lineage-specific gene loss and rapid evolution of a sperm- 231–255. specific ion channel complex: CatSpers and CatSperb. Crenshaw HC, Edelstein-Keshet L. 1993. Orientation by he- PLoS ONE 3: e3569. lical motion. II: Changing the direction of the axis of Carlson AE, Westenbroek RE, Quill T, Ren D, Clapham DE, motion. Bull Math Biol 55: 213–230. Hille B, Garbers DL, Babcock DF. 2003. CatSper1 re- Cukkemane A, Seifert R, Kaupp UB. 2011. Cooperative and 2þ quired for evoked Ca entry and control of flagellar uncooperative cyclic-nucleotide-gated ion channels. function in sperm. Proc Natl Acad Sci 100: 14864–14868. Trends Biochem Sci 36: 55–64. Carlson AE, Brelidze TI, Zagotta WN. 2013. Flavonoid reg- Darszon A, Nishigaki T, Beltran C, Trevino CL. 2011. Cal- ulation of EAG1 channels. J Gen Physiol 141: 347–358. cium channels in the development, maturation, and Caruso G, Bisegna P, Andreucci D, Lenoci L, Gurevich VV, function of spermatozoa. Physiol Rev 91: 1305–1355. Hamm HE, DiBenedetto E. 2011. Identification of key Denissenko P,Kantsler V,Smith DJ, Kirkman-Brown J. 2012. factors that reduce the variability of the single photon Human spermatozoa migration in microchannels reveals response. Proc Natl Acad 108: 7804–7807. boundary-following navigation. Proc Natl Acad Sci 109: Chavez JC, Ferreira JJ, Butler A, De La Vega Beltran JL, 8007–8010. Trevino CL, Darszon A, Salkoff L, Santi CM. 2014. þ Doan T, Mendez A, Detwiler PB, Chen J, Rieke F. 2006. SLO3 K channels control calcium entry through CATS- Multiple phosphorylation sites confer reproducibility of PER channels in sperm. J Biol Chem 289: 32266–32275. the rod’s single-photon responses. Science 313: 530–533. Chen Y, Cann MJ, Litvin TN, Iourgenko V, Sinclair ML, Duke TAJ, Bray D. 1999. Heightened sensitivity of a lattice of Levin LR, Buck J. 2000. Soluble adenylyl cyclase as an membrane receptors. Proc Natl Acad Sci 96: 10104– evolutionarily conserved bicarbonate sensor. Science 10108. 289: 625–628. Eisenbach M, Giojalas LC. 2006. Sperm guidance in mam- Chen SR, Chen M, Deng SL, Hao XX, Wang XX, Liu YX. mals—An unpaved road to the egg. Nat Rev Mol Cell Biol 2016. Sodium–hydrogen exchanger NHA1 and NHA2 7: 276–285. control sperm motility and male fertility. Cell Death Dis 7: e2152. Elgeti J, Gompper G. 2009. Self-propelled rods near surfaces Eur Phys Lett 85: 38002. Cherr GN, Morisawa M, Vines CA, Yoshida K, Smith EH, Matsubara T, Pillai MC, Griffin FJ, Yanagimachi R. 2008. Elgeti J, Kaupp UB, Gompper G. 2010. Hydrodynamics of Two egg-derived molecules in sperm motility initiation sperm cells near surfaces. Biophys J 99: 1018–1026. and fertilization in the Pacific herring (Clupea pallasi). Esposito G, Jaiswal BS, Xie F, Krajnc-Franken MAM, Rob- Int J Dev Biol 52: 743–752. ben TJAA, Strik AM, Kuil C, Philipsen RLA, van Duin M, Chung JJ, Navarro B, Krapivinsky G, Krapivinsky L, Clap- Conti M, et al. 2004. Mice deficient for soluble adenylyl ham DE. 2011. A novel gene required for male fertility cyclase are infertile because of a severe sperm-motility and functional CATSPER channel formation in sperma- defect. Proc Natl Acad Sci 101: 2993–2998. tozoa. Nat Commun 2: 153. Fechner S, Alvarez L, Bo¨nigk W,Mu¨ller A, Berger T,Pascal R, Chung JJ, Shim SH, Everley RA, Gygi SP, Zhuang X, Clap- Tro¨tschel C, Poetsch A, Stolting G, Siegfried KR, et al. þ 2þ ham DE. 2014. Structurally distinct Ca2þ signaling do- 2015. A K -selective CNG channel orchestrates Ca sig- mains of sperm flagella orchestrate tyrosine phosphory- nalling in zebrafish sperm. eLife 4: e07624. lation and motility. Cell 157: 808–822. Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Pal- Cook SP,Babcock DF.1993. Activation of Ca2þ permeability czewski K. 2003. Rhodopsin dimers in native disc mem- by cAMP is coordinated through the pHi increase in- branes. Nature 421: 127–128. duced by speract. J Biol Chem 268: 22408–22413. Galindo BE, Neill AT, Vacquier VD. 2005. A new hyper- Corkidi G, Taboada B, Wood CD, Guerrero A, Darszon A. polarization-activated, cyclic nucleotide-gated channel 2008. Tracking sperm in three-dimensions. Biochem Bio- from sea urchin sperm flagella. Biochem Biophys Res Com- phys Res Commun 373: 125–129. mun 334: 96–101. Cosson J, Huitorel P, Gagnon C. 2003. How spermatozoa Gauss R, Seifert R, Kaupp UB. 1998. Molecular identifica- come to be confined to surfaces. Cell Motil Cytoskel 54: tion of a hyperpolarization-activated channel in sea ur- 56–63. chin sperm. Nature 393: 583–587. Cosson J, Groison AL, Suquet M, Fauvel C, Dreanno C, Gestwicki JE, Kiessling LL. 2002. Inter-receptor communi- Billard R. 2008. Marine fish spermatozoa: Racing ephem- cation through arrays of bacterial chemoreceptors. Na- eral swimmers. Reproduction 136: 277–294. ture 415: 81–84. Crenshaw HC. 1990. Helical orientation—A novel mecha- Gross OP,Pugh EN Jr, Burns ME. 2012a. Calcium feedback nism for the orientation of microorganisms. In Biological to cGMP synthesis strongly attenuates single-photon re- motion (ed. Alt W,Hoffmann G), pp. 361–386. Springer, sponses driven by long rhodopsin lifetimes. Neuron 76: Berlin. 370–382.

16 Cite this article as Cold Spring Harb Perspect Biol 2016;9:a028225 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Sperm Sensory Signaling

Gross OP, Pugh EN Jr, Burns ME. 2012b. Spatiotemporal Kra¨hling AM, Alvarez L, Debowski K, Van Q, Gunkel M, cGMP dynamics in living mouse rods. Biophys J 102: Irsen S, Al-Amoudi A, Stru¨nker T, Kremmer E, Krause E, 1775–1784. et al. 2013. CRIS—A novel cAMP-binding protein con- Guerrero A, Nishigaki T, Carneiro J, Yoshiro T, Wood CD, trolling spermiogenesis and the development of flagellar Darszon A. 2010. Tuning sperm chemotaxis by calcium bending. PLoS Genet 9: e1003960. burst timing. Dev Biol 344: 52–65. Krasznai Z, Ma´ria´n T, Izumi H, Damjanovich S, Balkay L, Gunaratne HJ, Neill AT, Vacquier VD. 2006. Plasma mem- Tro´n L, Morisawa M. 2000. Membrane hyperpolarization brane calcium ATPase is concentrated in the head of sea removes inactivation of Ca2þ channels, leading to Ca2þ urchin spermatozoa. J Cell Physiol 207: 413–419. influx and subsequent initiation of sperm motility in the Gunkel M, Scho¨neberg J, Alkhaldi W, Irsen S, Noe F, Kaupp common carp. Proc Natl Acad Sci 97: 2052–2057. UB, Al-Amoudi A. 2015. Higher-order architecture of Lauga E, Powers TR. 2009. The hydrodynamics of swim- rhodopsin in intact photoreceptors and its implication ming microorganisms. Rep Prog Phys 72: 096601. for phototransduction kinetics. Structure 23: 628–638. Lee HC. 1984a. A membrane potential-sensitive Naþ–Hþ Haitin Y, Carlson AE, Zagotta WN. 2013. The structural exchange system in flagella isolated from sea urchin sper- mechanism of KCNH-channel regulation by the eag do- matozoa. J Biol Chem 259: 15315–15319. main. Nature 501: 444–448. Lee HC. 1984b. Sodium and proton transport in flagella Huber A, Sander P,Gobert A, Bahner M, Hermann R, Paul- isolated from sea urchin spermatozoa. J Biol Chem 259: sen R. 1996. The transient receptor potential protein 4957–4963. 2þ (Trp), a putative store-operated Ca channel essential Lee HC. 1985. The voltage-sensitive Naþ/Hþ exchange in for phosphoinositide-mediated photoreception, forms a sea urchin spermatozoa flagellar membrane vesicles stud- signaling complex with NorpA, InaC and InaD. EMBO J ied with an entrapped pH probe. J Biol Chem 260: 15: 7036–7045. 10794–10799. Hugentobler SA, Morris DG, Sreenan JM, Diskin MG. 2007. Lee HC, Garbers DL. 1986. Modulation of the voltage-sen- Ion concentrations in oviduct and uterine fluid and sitive Naþ/Hþ exchange in sea urchin spermatozoa blood serum during the estrous cycle in the bovine. Ther- through membrane potential changes induced by the iogenology 68: 538–548. egg peptide speract. J Biol Chem 261: 16026–16032. Jaiswal BS, Conti M. 2003. Calcium regulation of the soluble Lishko PV, Kirichok Y. 2010. The role of Hv1 and CatSper adenylyl cyclase expressed in mammalian spermatozoa. channels in sperm activation. J Physiol 588: 4667–4672. Proc Natl Acad Sci 100: 10676–10681. Lishko PV, Botchkina IL, Fedorenko A, Kirichok Y. 2010. Jaiswal D, Singh V, Dwivedi US, Trivedi S, Singh K. 2014. Acid extrusion from human spermatozoa is mediated Chromosome microarray analysis: A case report of infer- by flagellar voltage-gated proton channel. Cell 140: tile brothers with CATSPER gene deletion. Gene 542: 327–337. 263–265. Lishko PV, Botchkina IL, Kirichok Y. 2011. Progesterone Jansen V, Alvarez L, Balbach M, Stru¨nker T, Hegemann P, activates the principal Ca2þ channel of human sperm. Kaupp UB, Wachten D. 2015. Controlling fertilization and cAMP signaling in sperm by optogenetics. eLife 4: Nature 471: 387–391. e05161. Lishko PV,Kirichok Y,Ren D, Navarro B, Chung JJ, Clapham Jikeli JF,Alvarez L, Friedrich BM, Wilson LG, Pascal R, Colin DE. 2012. The control of male fertility by spermatozoan R, Pichlo M, Rennhack A, Brenker C, Kaupp UB. 2015. ion channels. Annu Rev Physiol 74: 453–475. Sperm navigation along helical paths in 3D chemoattrac- Liu J, Xia J, Cho KH, Clapham DE, Ren D. 2007. CatSperb,a tant landscapes. Nat Commun 6: 7985. novel transmembrane protein in the CatSper channel Kantsler V, Dunkel J, Blayney M, Goldstein RE. 2014. Cor- complex. J Biol Chem 282: 18945–18952. rection: Rheotaxis facilitates upstream navigation of Liu T,Huang JC, Zuo WL, Lu CL, Chen M, Zhang XS, Li YC, mammalian sperm cells. eLife 3: e03521. Cai H, Zhou WL, Hu ZY, et al. 2010. A novel testis-spe- þ þ Kaupp UB. 2010. Olfactory signalling in vertebrates and cific Na /H exchanger is involved in sperm motility insects: Differences and commonalities. Nat Rev Neurosci and fertility. Front Biosci (Elite Ed) 2: 566–581. 11: 188–200. Maddock JR, Shapiro L. 1993. Polar location of the chemo- Kaupp UB, Seifert R. 2002. Cyclic nucleotide-gated ion receptor complex in the Escherichia coli cell. Science 259: channels. Physiol Rev 82: 769–824. 1717–1723. Kaupp UB, Solzin J, Hildebrand E, Brown JE, Helbig A, Mannowetz N, Naidoo NM, Choo SA, Smith JF, Lishko PV. Hagen V, Beyermann M, Pampaloni F, Weyand I. 2003. 2013. Slo1 is the principal potassium channel of human The signal flow and motor response controlling chemo- spermatozoa. eLife 2: e01009. taxis of sea urchin sperm. Nat Cell Biol 5: 109–117. Matsumoto M, Solzin J, Helbig A, Hagen V, Ueno S-I, Ka- Kirichok Y, Navarro B, Clapham DE. 2006. Whole-cell wase O, Maruyama Y,Ogiso M, Godde M, Minakata H, et patch-clamp measurements of spermatozoa reveal an al- al. 2003. A sperm-activating peptide controls a cGMP- kaline-activated Ca2þ channel. Nature 439: 737–740. signaling pathway in starfish sperm. Dev Biol 260: 314– Kleinboelting S, Diaz A, Moniot S, van den Heuvel J, 324. Weyand M, Levin LR, Buck J, Steegborn C. 2014. Crystal Mendez A, Burns ME, Roca A, Lem J, Wu L-W, Simon MI, structures of human soluble adenylyl cyclase reveal Baylor DA, Chen J. 2000. Rapid and reproducible deac- mechanisms of catalysis and of its activation through tivation of rhodopsin requires multiple phosphorylation bicarbonate. Proc Natl Acad Sci 111: 3727–3732. sites. Neuron 28: 153–164.

Cite this article as Cold Spring Harb Perspect Biol 2016;9:a028225 17 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

D. Wachten et al.

Miki K, Clapham DE. 2013. Rheotaxis guides mammalian physics (ed. Stavenga DG, DeGrip WJ, Pugh ENJ), pp. sperm. Curr Biol 23: 443–452. 183–255. Elsevier, Amsterdam. Miller MR, Mansell SA, Meyers SA, Lishko PV.2015. Flagel- Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, lar ion channels of sperm: Similarities and differences Krapivinsky L, Kirichok Y,Ramsey IS, Quill TA,Clapham between species. Cell Calcium 58: 105–113. DE. 2007. All four CatSper ion channel proteins are re- Miller MR, Mannowetz N, Iavarone AT, Safavi R, Gracheva quired for male fertility and sperm cell hyperactivated EO, Smith JF, Hill RZ, Bautista DM, Kirichok Y, Lishko motility. Proc Natl Acad Sci 104: 1219–1223. PV. 2016. Unconventional endocannabinoid signaling Quill TA, Sugden SA, Rossi KL, Doolittle LK, Hammer RE, governs sperm activation via sex hormone progesterone. Garbers DL. 2003. Hyperactivated sperm motility driven Science 352: 555–559. by CatSper2 is required for fertilization. Proc Natl Acad Morisawa M. 2008. Adaptation and strategy for fertilization Sci 100: 14869–14874. in the sperm of teleost fish. J Appl Ichthyol 24: 362–370. Ramsey IS, Moran MM, Chong JA, Clapham DE. 2006. A Mukherjee S, Jansen V,Jikeli JF,Hamzeh H, Alvarez L, Dom- voltage-gated proton-selective channel lacking the pore browski M, Balbach M, Stru¨nker T, Seifert R, Kaupp UB, domain. Nature 440: 1213–1216. et al. 2016. A novel biosensor to study cAMP dynamics in Ren D, Navarro B, Perez G, Jackson AC, Hsu S, Shi Q, Tilly cilia and flagella. eLife 5: e14052. JL, Clapham DE. 2001. A sperm ion channel required for Navarro B, Kirichok Y, Clapham DE. 2007. KSper, a pH- sperm motility and male fertility. Nature 413: 603–609. sensitive Kþ current that controls sperm membrane po- Rich TC, Fagan KA, Nakata H, Schaack J, Cooper DMF, tential. Proc Natl Acad Sci 104: 7688–7692. Karpen JW. 2000. Cyclic nucleotide-gated channels co- Nishigaki T,Chiba K, Miki W,Hoshi M. 1996. Structure and localize with adenylyl cyclase in regions of restricted function of asterosaps, sperm-activating peptides from cAMP diffusion. J Gen Physiol 116: 147–161. the jelly coat of starfish eggs. Zygote 4: 237–245. Rich TC, Tse TE, Rohan JG, Schaack J, Karpen JW. 2001. In Nishigaki T, Jose O, Gonzalez-Cota AL, Romero F, Trevino vivo assessment of local phosphodiesterase activity using CL, Darszon A. 2014. Intracellular pH in sperm physiol- tailored cyclic nucleotide-gated channels as cAMP sen- ogy. Biochem Biophys Res Commun 450: 1149–1158. sors. J Gen Physiol 118: 63–77. Nolan MA, Babcock DF, Wennemuth G, Brown W, Burton Rothschild L. 1963. Non-random distribution of bull sper- KA, McKnight GS. 2004. Sperm-specific protein kinase A matozoa in a drop of sperm suspension. Nature 198: 1221–1222. catalytic subunit Ca2 orchestrates cAMP signaling for male fertility. Proc Natl Acad Sci 101: 13483–13488. Santi CM, Martinez-Lopez P,de la Vega-Beltran JL, Butler A, Nomura M, Beltra´n C, Darszon A, Vacquier VD. 2005. A Alisio A, Darszon A, Salkoff L. 2010. The SLO3 sperm- soluble adenylyl cyclase from sea urchin spermatozoa. specific potassium channel plays a vital role in male fer- Gene 353: 231–238. tility. FEBS Lett 584: 1041–1046. Ogawa H, Qui Y, Ogata CM, Misono KS. 2004. Crystal Sasaki M, Takagi M, Okamura Y. 2006. A voltage sensor- structure of hormone-bound atrial natriuretic peptide domain protein is a voltage-gated proton channel. Sci- receptor extracellular domain: Rotation mechanism for ence 312: 589592. transmembrane signal transduction. J Biol Chem 279: Schiffer C, Mu¨ller A, Egeberg DL, Alvarez L, Brenker C, 28625–28631. Rehfeld A, Frederiksen H, Wa¨schle B, Kaupp UB, Balbach Okunade GW,Miller ML, Pyne GJ, Sutliff RL, O’Connor KT, M, et al. 2014. Direct action of endocrine disrupting Neumann JC, Andringa A, Miller DA, Prasad V,Doetsch- chemicals on human sperm. EMBO Rep 15: 758–765. man T,et al. 2004. Targetedablation of plasma membrane Schneeweis DM, Schnapf JL. 1995. Photovoltage of rods and Ca2þ-ATPase (PMCA) 1 and 4 indicates a major house- cones in the macaque retina. Science 268: 1053–1056. keeping function for PMCA1 and a critical role in hyper- Schreiber M, WeiA, Yuan A, Gaut J, Saito M, Salkoff L. 1998. activated sperm motility and male fertility for PMCA4. J Slo3, a novel pH-sensitive Kþ channel from mammalian Biol Chem 279: 33742–33750. spermatocytes. J Biol Chem 273: 3509–3516. Oren-Benaroya R, Orvieto R, Gakamsky A, Pinchasov M, Schuh K, Cartwright EJ, Jankevics E, Bundschu K, Lieber- Eisenbach M. 2008. The sperm chemoattractant secreted mann J, Williams JC, Armesilla AL, Emerson M, Oceandy from human cumulus cells is progesterone. Hum Reprod D, Knobeloch KP, et al. 2004. Plasma membrane Ca2þ 23: 2339–2345. ATPase 4 is required for sperm motility and male fertility. Perez-Cerezales S, Boryshpolets S, Afanzar O, Brandis A, J Biol Chem 279: 28220–28226. Nevo R, Kiss V,Eisenbach M. 2015. Involvement of opsins Scott K, Zuker C. 1998. TRP,TRPL and trouble in photore- in mammalian sperm thermotaxis. Sci Rep 5: 16146. ceptor cells. Curr Opinion Neurobiol 8: 383–388. Pichlo M, Bungert-Plu¨mke S, Weyand I, Seifert R, Bo¨nigk W, Seifert R, Flick M, Bo¨nigk W,Alvarez L, Tro¨tschel C, Poetsch Stru¨nker T,Kashikar ND, Goodwin N, Mu¨ller A, Pelzer P, A, Mu¨ller A, Goodwin N, Pelzer P, Kashikar ND, et al. et al. 2014. High density and ligand affinity confer ultra- 2015. The CatSper channel controls chemosensation in sensitive signal detection by a guanylyl cyclase chemore- sea urchin sperm. EMBO J 34: 379–392. ceptor. J Cell Biol 206: 541–557. Servin-Vences MR, Tatsu Y,Ando H, Guerrero A, Yumoto N, Potter LR. 2011. Guanylyl cyclase structure, function and Darszon A, Nishigaki T. 2012. A caged progesterone an- regulation. Cell Signal 23: 1921–1926. alog alters intracellular Ca2þ and flagellar bending in Pugh ENJ, Lamb TD. 2000. Phototransduction in vertebrate human sperm. Reproduction 144: 101–109. rods and cones: Molecular mechanisms of amplification, Shiba K, Baba SA, Inoue T, Yoshida M. 2008. Ca2þ bursts recovery and light adaptation. In Handbook of biological occur around a local minimal concentration of attractant

18 Cite this article as Cold Spring Harb Perspect Biol 2016;9:a028225 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Sperm Sensory Signaling

and trigger sperm chemotactic response. Proc Natl Acad Vines CA, Yoshida K, Griffin FJ, Pillai MC, Morisawa M, Sci 105: 19312–19317. Yanagimachi R, Cherr GN. 2002. Motility initiation in Smith JF, Syritsyna O, Fellous M, Serres C, Mannowetz herring sperm is regulated by reverse sodium–calcium N, Kirichok Y, Lishko PV. 2013. Disruption of the prin- exchange. Proc Natl Acad Sci 99: 2026–2031. cipal, progesterone-activated sperm Ca2þ channel in a Visconti PE, Moore GD, Bailey JL, Leclerc P, Connors SA, CatSper2-deficient infertile patient. Proc Natl Acad Sci Pan D, Olds-Clarke P, Kopf GS. 1995. Capacitation of 110: 6823–6828. mouse spermatozoa. II: Protein tyrosine phosphoryla- Sourjik V, Berg HC. 2004. Functional interactions between tion and capacitation are regulated by a cAMP-dependent receptors in bacterial chemotaxis. Nature 428: 437– pathway. Development 121: 1139–1150. 441. WangD, King SM, Quill TA,Doolittle LK, Garbers DL. 2003. þ þ Steegborn C, Litvin TN, Levin LR, Buck J, Wu H. 2005. A new sperm-specific Na /H exchanger required Bicarbonate activation of adenylyl cyclase via promotion for sperm motility and fertility. Nat Cell Biol 5: 1117– of catalytic active site closure and metal recruitment. Nat 1122. Struct Mol Biol 12: 32–37. WangD, Hu J, Bobulescu IA, Quill TA,McLeroy P,Moe OW, þ þ Stru¨nker T, Weyand I, Bo¨nigk W, Van Q, Loogen A, Brown Garbers DL. 2007. A sperm-specific Na /H exchanger JE, Kashikar N, Hagen V, Krause E, Kaupp UB. 2006. A (sNHE) is critical for expression and in vivo bicarbonate Kþ-selective cGMP-gated ion channel controls chemo- regulation of the soluble adenylyl cyclase (sAC). Proc Natl sensation of sperm. Nat Cell Biol 8: 1149–1154. Acad Sci 104: 9325–9330. Stru¨nker T,Goodwin N, Brenker C, Kashikar ND, Weyand I, Wang H, Liu J, Cho KH, Ren D. 2009. A novel, single, trans- Seifert R, Kaupp UB. 2011. The CatSper channel medi- membrane protein CATSPERG is associated with CATS- ates progesterone-induced Ca2þ influx in human sperm. PER1 channel protein. Biol Reprod 81: 539–544. Nature 471: 382–386. Wennemuth G, Babcock DF, Hille B. 2003a. Calcium clear- Su YH, Vacquier VD. 2002. A flagellar Kþ-dependent Naþ/ ance mechanisms of mouse sperm. J Gen Physiol 122: Ca2þ exchanger keeps Ca2þ low in sea urchin spermato- 115–128. zoa. Proc Natl Acad Sci 99: 6743–6748. Wennemuth G, Carlson AE, Harper AJ, Babcock DF. 2003b. 2þ Su YH, Vacquier VD. 2006. Cyclic GMP-specific phospho- Bicarbonate actions on flagellar and Ca -channel re- diesterase-5 regulates motility of sea urchin spermatozoa. sponses: initial events in sperm activation. Development Mol Biol Cell 17: 114–121. 130: 1317–1326. Su TW,Xue L, Ozcan A. 2012. High-throughput lensfree 3D Wertheimer E, Krapf D, de la Vega-Beltran JL, Sanchez-Car- tracking of human sperms reveals rare statistics of helical denas C, Navarrete F, Haddad D, Escoffier J, Salicioni trajectories. Proc Natl Acad Sci 109: 16018–16022. AM, Levin LR, Buck J, et al. 2013. Compartmentalization Suarez SS. 2008. Control of hyperactivation in sperm. Hum of distinct cAMP signaling pathways in mammalian Reprod Update 14: 647–657. sperm. J Biol Chem 288: 35307–35320. Suarez SS, Varosi SM, Dai X. 1993. Intracellular calcium Whitlock GG, Lamb TD. 1999. Variability in the time course increases with hyperactivation in intact, moving hamster of single photon responses from toad rods: Termination sperm and oscillates with the flagellar beat cycle. Proc of rhodopsin’s activity. Neuron 23: 337–351. Natl Acad Sci 90: 4660–4664. Wilson EM, Chinkers M. 1995. Identification of sequences Takai H, Morisawa M. 1995. Change in intracellular Kþ mediating guanylyl cyclase dimerization. Biochemistry concentration caused by external osmolality change reg- 34: 4696–4701. ulates sperm motility of marine and freshwater teleosts. J Winet H, Bernstein GS, Head J. 1984. Observations on the Cell Sci 108: 1175–1181. response of human spermatozoa to gravity, boundaries Tavares RS, Mansell S, Barratt CL, Wilson SM, Publicover and fluid shear. J Reprod Fertil 70: 511–523. SJ, Ramalho-Santos J. 2013. p,p0-DDE activates CatSper WoodCD, Nishigaki T,Furuta T,Baba SA, Darszon A. 2005. and compromises human sperm function at environ- Real-time analysis of the role of Ca2þ in flagellar move- mentally relevant concentrations. Hum Reprod 28: ment and motility in single sea urchin sperm. J Cell Biol 3167–3177. 169: 725–731. Teves ME, Barbano F, Guidobaldi HA, Sanchez R, Miska W, Yanagimachi R, Cherr G, Matsubara T, Andoh T, Harumi T, Giojalas LC. 2006. Progesterone at the picomolar range is Vines C, Pillai M, Griffin F,Matsubara H, Weatherby T,et a chemoattractant for mammalian spermatozoa. Fertil al. 2013. Sperm attractant in the micropyle region of fish Steril 86: 745–749. and insect eggs. Biol Reprod 88: 47. Teves ME, Guidobaldi HA, Unates DR, Sanchez R, Miska W, YangC, Zeng XH, Zhou Y,Xia XM, Lingle CJ. 2011. LRRC52 Publicover SJ, Morales Garcia AA, Giojalas LC. 2009. (leucine-rich-repeat-containing protein 52), a testis-spe- Molecular mechanism for human sperm chemotaxis me- cific auxiliary subunit of the alkalization-activated Slo3 diated by progesterone. PLoS ONE 4: e8211. channel. Proc Natl Acad Sci 108: 19419–19424. Tsunoda S, Sierralta J, Sun Y, Bodner R, Suzuki E, Becker A, Yau KW, Hardie RC. 2009. Phototransduction motifs and Socolich M, Zuker CS. 1997. A multivalent PDZ-domain variations. Cell 139: 246–264. protein assembles signalling complexes in a G-protein- Yu H, Olshevskaya E, Duda T, Seno K, Hayashi F, Sharma coupled cascade. Nature 388: 243–249. RK, Dizhoor AM, Yamazaki A. 1999. Activation of Vaandrager AB. 2002. Structure and function of the heat- retinal guanylyl cyclase-1 by Ca2þ-binding proteins stable enterotoxin receptor/guanylyl cyclase C. Mol Cell involves its dimerization. J Biol Chem 274: 15547– Biochem 230: 73–83. 15555.

Cite this article as Cold Spring Harb Perspect Biol 2016;9:a028225 19 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

D. Wachten et al.

Zeng XH, Yang C, Kim ST, Lingle CJ, Xia XM. 2011. Dele- KSPER currents and is critical for normal fertility. Proc tion of the Slo3 gene abolishes alkalization-activated Kþ Natl Acad Sci 112: 2599–2604. current in mouse spermatozoa. Proc Natl Acad Sci 108: Zhang Y,Malekpour M, Al-Madani N, Kahrizi K, Zanganeh 5879–5884. M, Lohr NJ, Mohseni M, Mojahedi F,Daneshi A, Najma- Zeng XH, Navarro B, Xia XM, Clapham DE, Lingle CJ. 2013. badi H, et al. 2007. Sensorineural deafness and male in- Simultaneous knockout of Slo3 and CatSper1 abolishes fertility: A contiguous gene deletion syndrome. J Med all alkalization- and voltage-activated current in mouse Genet 44: 233–240. spermatozoa. J Gen Physiol 142: 305–313. Zhang Z, Liu J, Meriano J, Ru C, Xie S, Luo J, Sun Y. 2016. Zeng XH, Yang C, Xia XM, Liu M, Lingle CJ. 2015. SLO3 Human sperm rheotaxis: a passive physical process. Sci auxiliary subunit LRRC52 controls gating of sperm Rep 6: 23553.

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Sperm Sensory Signaling

Dagmar Wachten, Jan F. Jikeli and U. Benjamin Kaupp

Cold Spring Harb Perspect Biol 2017; doi: 10.1101/cshperspect.a028225 originally published online January 6, 2017

Subject Collection Cilia

Ciliary Mechanisms of Cyst Formation in Cilia in Left−Right Symmetry Breaking Polycystic Kidney Disease Kyosuke Shinohara and Hiroshi Hamada Ming Ma, Anna-Rachel Gallagher and Stefan Somlo Photoreceptor Cilia and Retinal Ciliopathies Discovery, Diagnosis, and Etiology of Craniofacial Kinga M. Bujakowska, Qin Liu and Eric A. Pierce Ciliopathies Elizabeth N. Schock and Samantha A. Brugmann G-Protein-Coupled Receptor Signaling in Cilia Axoneme Structure from Motile Cilia Kirk Mykytyn and Candice Askwith Takashi Ishikawa Evolution of Cilia Cilia and Ciliopathies in Congenital Heart Disease David R. Mitchell Nikolai T. Klena, Brian C. Gibbs and Cecilia W. Lo Transition Zone Migration: A Mechanism for Sperm Sensory Signaling Cytoplasmic Ciliogenesis and Postaxonemal Dagmar Wachten, Jan F. Jikeli and U. Benjamin Centriole Elongation Kaupp Tomer Avidor-Reiss, Andrew Ha and Marcus L. Basiri Cilia and Obesity Primary Cilia and Coordination of Receptor Christian Vaisse, Jeremy F. Reiter and Nicolas F. Tyrosine Kinase (RTK) and Transforming Growth Berbari Factor β (TGF-β) Signaling Søren T. Christensen, Stine K. Morthorst, Johanne B. Mogensen, et al. Posttranslational Modifications of Tubulin and Primary Cilia and Mammalian Hedgehog Signaling Cilia Fiona Bangs and Kathryn V. Anderson Dorota Wloga, Ewa Joachimiak, Panagiota Louka, et al.

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Radial Spokes−−A Snapshot of the Motility Cilia and Mucociliary Clearance Regulation, Assembly, and Evolution of Cilia and Ximena M. Bustamante-Marin and Lawrence E. Flagella Ostrowski Xiaoyan Zhu, Yi Liu and Pinfen Yang

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