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Home , MCOLN3, Polycystin 1, Polycystin 2, Receptor potential, TRPA (ion channel), TRPC

J Am Soc Nephrol 15: 1690–1699, 2004 The Transient Potential Superfamily of Channels

CHOU-LONG HUANG Division of Nephrology, Department of Medicine, and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas

Abstract. The transient receptor potential (TRP) superfamily of and have diverse functions, ranging from thermal, tactile, , is cation-selective ion channels with six predicted osmolar, and fluid flow sensing to transepithelial Ca2ϩ and transmembrane segments and intracellularly localized amino Mg2ϩ transport. of TRP proteins produce many and carboxyl termini. Members of the TRP superfamily are renal diseases, including Mg2ϩ wasting, hypocalcemia, and identified on the basis of amino sequence and structural polycystic diseases. This review focuses on recent similarity and are classified into TRPC, TRPV, TRPM, TRPP, advances in the understanding of their functions. TRPN, and TRPML subfamilies. TRP channels are widespread

The first transient receptor potential (TRP) was discov- TRPC, TRPV, and TRPM subfamilies. More recent classifica- ered in studies that examined phototransduction tion has expanded TRP superfamily to include three additional, (1). The photoreceptor cells of Drosophila exhibit sustained more distantly related subfamilies, TRPP, TRPML, and TRPN receptor potentials in response to continuous light exposure. (Figure 1). Structurally, all of these TRP channels have six The ionic basis for the sustained receptor potentials is influx of predicted transmembrane (TM) segments and N-terminal and Ca2ϩ from the extracellular space. Cosens and Manning (1) C-terminal cytoplasmic tails similar to topologies of voltage- reported in 1969 that one group of mutant flies exhibits TRP gated Kϩ,Naϩ, and Ca2ϩ channels; cyclic nucleotide-gated upon continuous light exposure and named it trp, for transient channels; and hyperpolarization-activated channels (Figure 2). receptor potential. The trp was cloned in 1989 (2) and The fourth TM segment of TRP channels lacks the complete subsequently shown to encode a Ca2ϩ-permeable cation chan- set of positively charged residues necessary for voltage sensing nel (3). Since then, many channels that bear sequence and in many voltage-gated channels. The six TM polypeptide sub- structural similarities to the Drosophila TRP have been cloned units of TRP channels likely assemble as tetramers to form from flies, worms, and . Together, they form the TRP cation-permeable pores. Across the entire superfamily, the superfamily. sequence identity is only ~20%. The similarity Ion channels (e.g., voltage-gated Kϩ channels) are typically between subfamilies is limited primarily to the transmembrane identified by their modes of activation and/or ion selectivity. segments. Within each TRP subfamily, amino acid sequence Each family or superfamily of ion channels of similar activa- similarity is much higher and extends along the entire polypep- tion and selectivity consists of multiple members of channel tide. The N-terminal cytoplasmic region of some subfamilies proteins with amino acid . Unlike most ion contains several -binding repeats (Figure 2). Ankyrin- channel families, the TRP superfamily of ion channels are binding repeats are 33-residue motifs that mediate cytoskeletal identified on the basis of homology only. The mode of activa- anchoring or protein–protein interaction. Some subfamilies tion and selectivity for TRP channels are disparate. Some TRP contain a conserved stretch of 25 amino , called the TRP channels are activated by ligands, whereas others are regulated domain, or a or phosphatase domain in the C-terminal by physical stimuli (e.g., heat) or yet-unknown mechanisms. cytoplasmic region. All TRP channels are cation selective, but the selectivity ratio 2ϩ ϩ for Ca versus the monovalent cation Na (PCa/PNa) varies Ͼ Ͻ Molecular Identification and Characterization widely, ranging from 100:1, to 1 to 10:1, to 0.05:1. The of TRP Channels lack of common identifying features has in part contributed to The TRPC Subfamily the confusing nomenclature of TRP channels in the literature. The TRPC (for canonical TRP) subfamily is composed of A recent consensus report proposed a unified nomenclature proteins that are most highly related to Drosophila TRP. It for the TRP superfamily (4). It classified TRP channels into consists of seven mammalian members, TRPC1 to 7 (5–10). Members of the TRPC subfamily contain three to four ankyrin repeats in the N-terminus and a conserved TRP domain in the Correspondence to Dr. Chou-Long Huang, Department of Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8856. Phone: 214- C-terminus (Figure 2). TRPC subfamily can be divided 648-8627; Fax: 214-648-2071; E-mail: [email protected] into three subgroups on the basis of amino acid homology: 1046-6673/1507-1690 TRPC1, TRPC4/5, and TRPC3/6/7. TRPC2 is a in Journal of the American Society of Nephrology human but seems to encode an expressed protein in rat and Copyright © 2004 by the American Society of Nephrology mouse (8–10). TRPC4 and TRPC5 share ~65% homology. DOI: 10.1097/01.ASN.0000129115.69395.65 TRPC3, TRPC6, and TRPC7 share ~70 to 80% homology. J Am Soc Nephrol 15: 1690–1699, 2004 TRP Channels 1691

Members of the TRPC subfamily are highly expressed in and to lesser degrees in many periph- eral tissues, including kidney. The selectivity ratio for Ca2ϩ ϩ versus Na (PCa/PNa) for TRPC channels ranges from 0.5 to 10:1. TRPC channels are involved in Ca2ϩ entry in response to activation of C (PLC) by membrane receptors and thus play important roles in the regulation of intracellular Ca2ϩ concentration by hormones and growth factors (see Func- tions of TRP Channels).

The TRPV Subfamily The TRPV subfamily is named after the first mammalian member of the subfamily, vanilloid receptor 1 (VR1). It con- tains six mammalian members, TRPV1 to 6. TRPV1 (VR1) was isolated by expression cloning using , a vanilloid compound derived from “hot” pepper, as a binding (11). TRPV2 to 4 were isolated by searching for expressed sequence tags (EST) with amino acid homology to TRPV1 (12–16). TRPV1 to 4 share 40 to 50% amino acid homology, are 2ϩ Ca -permeable nonselective cation channels (PCa/PNa ~3 to 10:1), and have steep sensitivity. TRPV5 and TRPV6 were isolated by expression cloning of proteins that mediate Ca2ϩ transport in kidney and intestine, respectively (17,18). They are the most highly Ca2ϩ-selective TRP channels Ͼ (PCa/PNa 100:1). Overall, TRPV subfamily channels contain three to four ankyrin repeats in the N-terminus and a TRP domain in the C-terminus (Figure 2). TRPV channels are also present in invertebrates. Invertebrate TRPV proteins include C. elegans OSM-9 and OCR (for OSM-9/capsaicin receptor re- lated) (19,20). OSM-9 is more closely related to TRPV5/6 than TRPV1 to 4 at the amino acid level.

The TRPM Subfamily The TRPM subfamily is named after the founding member, Figure 1. Classification of the transient receptor potential (TRP) melastatin. Melastatin, TRPM1, is a tumor suppressor protein superfamily. isolated in a screen for whose level of expression (in- versely) correlated with the severity of metastatic potential of a cell line (21). There are eight mammalian mem- bers in the TRPM subfamily. TRPM subfamily channels lack ankyrin repeats in the N-terminus but contain the TRP domain in the C-terminus (Figure 2). The C-terminus of TRPM pro- teins is considerably longer than the corresponding region of other TRP. The C-terminus of several members of TRPM contains enzyme domains. These TRPM proteins are thus called “chanzymes.” TRPM2 (initially called TRPC7 and LTRPC2) is a Ca2ϩ- permeable channel that contains a C-terminal ADP-ribose py- rophosphatase domain (22–25). ADP-ribose pyrophosphatase catalyzes the hydrolysis of nucleoside diphosphate derivatives. The domain in TRPM2, however, is an ineffective hydrolase but binds ADP-ribose and NAD (23–25). ADP-ribose and NAD directly activate TRPM2 to allow Ca2ϩ influx. ATP counteracts the NAD-induced activation. TRPM2 is also reg- ␣ ulated by H2O2 and TNF- (26,27). Thus, TRPM2 may be Figure 2. Domain organization of TRP channels. The TRP domain is important in sensing oxidative stress and in linking a highly conserved 25–amino acid region. The region identified as with the metabolism of ADP-ribose and NAD. ϩ “TRP box” is nearly invariant. X denotes any amino acid. TRPM3 is a Ca2 -permeable, nonselective cation channel 1692 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1690–1699, 2004 whose activity is increased by hypotonicity (28). TRPM4 and Functions of TRP Channels TRPM5 are the only TRP channels that are permeable to The TRP superfamily comprises a large number of ion 2ϩ Ͻ monovalent cations but not Ca (PCa/PNa 0.05:1) (29,30). channels with diverse functions. The division into subfamilies ϩ However, they are activated by intracellular Ca2 (29,30). on the basis of amino acid sequence and structural similarity ϩ Activation of TRPM4 and TRPM5 by intracellular Ca2 leads does not provide functional classification for TRP proteins. For to membrane . TRPM6 and TRPM7 both contain example, members of the TRPV subfamily are involved in a C-terminal protein kinase domain (31–36). The role of these thermal and nociceptive sensing as well as transporting Ca2ϩ in kinase domains in the channel function of TRPM6 and TRPM7 epithelial tissues. Moreover, thermal sensing is not restricted to is not known. TRPM8 is an outward rectifying channel that can members of the TRPV subfamily. TRPM8 also functions in be activated by cold (37,38). It was isolated by expression thermal sensing. In this section, TRP channels are discussed on cloning of a receptor from sensory . the basis of their functions.

The TRPP Subfamily ϩ The TRPP subfamily is so named because of its founding Role of TRP in PLC-Dependent Ca2 Influx member, PKD2. PKD2 (also called TRPP2) was discovered as In virtually all eukaryotic cells, activation of PLC-coupled one of the gene products mutated in autosomal dominant membrane receptors by hormones leads to an increase in in- polycystic kidney disease (39). PKD2 is a six-TM protein that tracellular Ca2ϩ. Activation of PLC hydrolyzes phosphatidyl- shares ~25% amino acid identity with the closely related inositol 4,5-bisphosphate to generate inositol 1,4,5-trisphos-

TRPC3 and TRPC6 over the region spanning TM segments IV phate (IP3) and diacylglycerol (DAG). The increase in through VI (40). Mammalian PKD2 is a Ca2ϩ-permeable, intracellular Ca2ϩ is initially produced by release of Ca2ϩ from 2ϩ nonselective cation channel (41). It contains a Ca -binding intracellular IP3-sensitive stores and is followed by an influx of EF-hand motif and a coiled-coil domain in the C-terminus but Ca2ϩ from the extracellular space through plasma membrane does not include any ankyrin repeats or a TRP domain. Ca2ϩ-permeable channels. The entry of Ca2ϩ from the extra- PKD2L1 (TRPP3) and PKD2L2 (TRPP5) are homologues of cellular space is important for refilling intracellular stores. The PKD2 (42,43). No mutations in either PKD2L1 or PKD2L2 mechanism for Ca2ϩ entry has been studied extensively. In one have been found in patients with autosomal dominant polycys- mechanism, termed “store-operated Ca2ϩ entry,” the emptying tic kidney disease. of intracellular stores activates surface membrane Ca2ϩ chan- The much longer PKD1 protein (TRPP1) is an 11-TM pro- nels via either diffusible factors or a direct interaction between 2ϩ 2ϩ tein (44). The last six TM segments of PKD1 are homologous IP3 receptors and surface Ca channels (55–57). These Ca - to PKD2 and other related TRP channels (45). PKD1 is not permeable channels on the cell surface are called store-oper- known to form a channel by itself but may complex with PKD2 ated channels (SOC). Not all Ca2ϩ entry after PLC activation to regulate its channel activity (46). is dependent on store depletion. Ca2ϩ entry may also be due to activation of surface Ca2ϩ channels by other intracellular sec- The TRPN Subfamily ond messengers, such as DAG. The first member of the TRPN subfamily is Drosophila Store-operated Ca2ϩ entry is widespread and represents the NOMPC protein. NOMPC is the gene product of mutant flies major mechanism of regulation of Ca2ϩ influx in nonexcitable with the phenotype of “no potentials” cells such as renal tubule cells. Because of their prevalence and (47,48). The Drosophila NOMPC protein shares significant importance, considerable effort has been devoted to identifying homology with the TRP superfamily. The N-terminus of SOC and to understanding the mechanism of activation. The NOMPC contains 29 ankyrin repeats (Figure 2). A NOMPC discovery that Drosophila TRP proteins were PLC-dependent orthologue was also identified in C. elegans (48) and in ze- Ca2ϩ influx channels has fueled much of the interests and brafish (49). No TRPN have been found in mammals. hopes for isolation of SOC. TRPC channels are the closest relatives of Drosophila TRP and all are activated by – The TRPML Subfamily coupled receptors. A vast number of papers have reported that The TRPML subfamily is defined by a human protein, many TRPC channels function as SOC. Zhu et al. (7) first mucolipin 1. Mucolipin 1 (TRPML1) is a 580–amino acid long reported that expression of human TRPC3 in cultured human protein probably restricted to intracellular vesicles (50–52). embryonic kidney (HEK) cells gives rise to - and thap- TRPML1 contains two proline-rich regions, a lipase serine sigargin-activated channel activity. Because thapsigargin de- active site in the N-terminus and a dileucine motif suggestive pletes intracellular Ca2ϩ stores by inhibiting the endoplasmic of lysosomal targeting in the C-terminus. Mutations in reticulum Ca2ϩ-ATPase, the authors concluded that TRPC3 TRPML1 cause mucolipidosis type IV (MLIV), a rare autoso- proteins constitute subunits of SOC. Others have also reported mal recessive lysosomal storage disease that affects , that reduction of TRPC1 expression using antisense oligonu- eyes, and gastric function. The defect in MLIV seems to be in cleotides leads to inhibition of endogenous SOC (58). A dom- sorting or transport of intracellular vesicles. Channel function inant-negative form of TRPC3 inhibits store-operated Ca2ϩ of TRPML1 has recently been reported (53). TRPML2 and 3 entry in umbilical vein endothelial cells (59). were also identified (54). TRPML3 is present in the Kiselyov et al. (60) reported that in HEK cells that stably of hair cells and the plasma membrane of stereocilia. express human TRPC3, IP3 activates single channels in excised J Am Soc Nephrol 15: 1690–1699, 2004 TRP Channels 1693 inside-out patches. This activation is lost upon extensive wash- threshold (Ն25°C) (71) and is capable of integrating a large ing of excised patches and is restored by addition of IP3-bound number of stimuli (72) (see below). Both TRPV3 and TRPV4 IP3 receptor. Kiselyov et al. concluded that TRPC3 is a store- are present in sensory neurons and in , where they operated channel that is activated via direct interaction with IP3 might function as thermal in the . receptors. Similar store-operated channel activity has been Further evidence that TRP proteins are essential thermal reported for TRPC4 and TRPC7 channels (61,62). Recently, sensors comes from recent discovery that other TRP proteins knockout mice that lack the TRPC4 gene have been created function as receptors for cold. TRPM8, isolated by expression (61). TRPC4Ϫ/Ϫ mice exhibit impaired vasorelaxation of aor- cloning of a menthol receptor, is activated by cold (8 to 28°C) tic rings; aortic endothelial cells isolated from knockout mice (37,38). Its activation by menthol produces the cooling sensa- exhibit defective store-operated Ca2ϩ entry (61), providing tion of the compound. TRPM8 is found in ~10% of DRG or support that TRPC4 channels function as SOC. TG neurons. Cold below 28°C evoke large cur- However, many publications also dispute the conclusion that rents through TRPM8, which saturates near 8°C. Knowing that TRPC proteins are SOC. For example, Zitt et al. (63) reported some neurons are activated only by noxious cold temperature that TRPC3 expressed in Chinese hamster (CHO) cells is (Ͻ17°C), Story et al. (73) searched for additional cold sensors not store dependent but rather is activated by DAG. Hofmann and found a unique protein named ANKTM1. ANKTM1 is et al. (64) confirmed these findings and reported that TRPC3 found in and mice and is distantly related to the and TRPC6 are activated by DAG. Drosophila TRP proteins, invertebrate TRPN subfamily but has little sequence similarity the earliest and most promising candidates for SOC, have now to other mammalian TRP proteins (Table 1). It may be con- been shown definitively not to be store dependent. Mutant flies sidered the founding member of a new subfamily, TRPA (not that lack the IP3 receptor gene remain capable of generating shown in the phylogenetic tree in Figure 1). ANKTM1 is normal sustained receptor potentials on continuous light expo- expressed in a subset of sensory neurons that also express sure (65). It is now believed that Drosophila TRP proteins are TRPV1. activated by DAG, polyunsaturated fatty acids (downstream In summary, at least six TRP proteins are involved in tem- metabolites of DAG), and/or a reduction of phosphatidylino- perature sensing. The unique threshold for activation but over- sitol 4,5-bisphosphate2 (66,67). Thus, the question of whether lapping range of sensitivity for these proteins allows organisms and which TRP constitutes SOC remains unsettled. The rea- to have a combinatorial mode of thermal coding that responds son(s) for the differences among these studies is not known. to temperatures that span between 8 and 60°C. Thus, noxious One possibility is that different expression systems were used cold temperatures activate ANKTM1 and TRPM8, whereas in these studies. Because virtually every cell expresses some cool temperatures activate TRPM8 alone. Warm temperatures TRP proteins endogenously, expressed exogenous proteins activate TRPV3 and TRPV4, whereas moderate noxious heat may form heteromultimers with endogenous proteins and/or activates TRPV1 and high noxious heat activates TRPV1 and activate endogenous TRP proteins. Irrespective of the mecha- TRPV2. nism of activation (store dependent or store independent), it is clear that TRPC play an important role in PLC-dependent Ca2ϩ TRP as Mechanosensors entry. is the basis for , osmolar sensing, stretch, touch, and flow sensing (74). Hearing is initiated by the TRP as Thermal and Noxious Receptors bending of cilia on the hair cells in response to TRPV1 was first identified as a receptor that binds capsa- incoming sound waves. Bending of cilia activates “transduc- icin. Capsaicin is an ingredient of chili peppers that produces tion channels” that convert the mechanical to electri- the “hot,” spicy sensation. Capsaicin sensitivity is a functional cal signals, which travel by the auditory nerve fibers to the hallmark of nociceptive sensory neurons. Consistent with this brain. Vestibular hair cells in the semicircular canals contain concept, TRPV1 is expressed in primary afferent sensory neu- similar types of transduction channels to sense movement of rons of the (DRG) and trigeminal ganglion the head. (TG) (68). Binding of capsaicin activates TRPV1. TRPV1 is The best studied mechanosensitive channel is the bacterial also activated by noxious heat (Ն43°C) and low pH (5.9) (68). MscL channel (75). The MscL channel is a mechanosensitive Gating by heat is direct, whereas low pH reduces the temper- channel that is activated by lateral membrane tension. The ature threshold for activation. In addition, inflammatory medi- existence of these channels in Archaebacteria highlights the ators activate TRPV1 (69,70). Because tissue injury produces ancient nature of mechanotransduction and its critical role in acidosis and , TRPV1 is a polymodal detector of all cells. No MscL homologues have been identified in eu- injury. karyotes. Eukaryotic mechanosensitive channels include at TRPV2 is ~50% identical to TRPV1 but is insensitive to least two unrelated gene families, the DEG/ENaC (degenerins/ capsaicin and low pH (12). Instead, it is activated by heat at a epithelial Naϩ channels) superfamily (reviewed in ref. 74) and higher temperature threshold than TRPV1 (Ն52°C). TRPV3 is the TRP superfamily. The TRP superfamily of proteins con- temperature sensitive in the physiologic temperature range (31 tributes to all modalities of mechanosensation from flies, to 39°C) (13–15). TRPV4 was first described as a channel that worms, and fish to humans. The first cloned TRP channel was activated by hypotonicity-induced cell swelling (16). implicated in mechanosensation is the C. elegans OSM-9 of TRPV4 is also temperature sensitive but at a low activation the TRPV subfamily. Worms with mutations in the osm-9 gene 1694 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1690–1699, 2004

Table 1. Functions of mammalian TRP proteinsa

TRPC (1–7) PLC-dependent Ca2ϩ influx in CNS and peripheral tissues including kidney; TRPC1 can associate with TRPP2 (PKD2) TRPV 1 Thermal receptor (activated by T Ն43°C); noxious receptor (activated by inflammatory mediators, by low pH) 2 Thermal receptor (activated by T Ն52°C) 3 Thermal receptor (activated by T 31 to 39°C) 4 Thermal receptor (activated by T Ն25°C); noxious receptor (activated by inflammatory mediators); mechanoreceptor (osmolar sensing and noxious mechanical stimulus) 5 Epithelial Ca2ϩ transport 6 Epithelial Ca2ϩ transport (forms heteromultimers with V5); cell growth control (upregulated in ) TRPM 1 Cell growth control (a tumor suppressor downregulated in metastatic melanoma) 2 Contains an ADP-ribose and NAD binding domain; may be important in sensing oxidative stress and linking apoptosis to cellular NAD metabolism 3 Possible mechanosensor (activated by hypotonicity) 4 Activated by high intracellular Ca2ϩ; may be important in regulation of by intracellular Ca2ϩ 5 May be a taste 6 Epithelial Mg2ϩ transport 7 May form heteromultimers with TRPM6 in kidney; cellular uptake of divalent cations in every cell (essential for cell viability) 8 Cold receptor (activated byT8to28°C); cell growth control (upregulated in ) ANKTM1 Cold receptor (activated by T Յ17°C) TRPP (1–5) P1 (PKD1) and P2 (PKD2) are important in ciliary mechanosensation; mutations of P1 and P2 cause polycystic kidney disease TRPML 1 Sorting or transport of intracellular vesicles (mutations of TRPML1 cause mucolipidosis type IV) 3 May be mechanosensor (present in the plasma membrane of stereocilia of hair cells; mutations cause deafness in mice)

a TRP, transient receptor potential; PLC, ; CNS, central nervous system. are defective in osmotic avoidance, sensitivity to nose touch, osmolarity during water restriction and a lower serum vaso- and attraction to volatile odorants (19). NOMPC, a member of pressin level during hyperosmolar challenge. Urine osmolarity TRPN, is located in mechanosensory bristles and is essential is not different between knockout mice and control littermates for response to touch stimuli in flies (47,48). In , receiving dDAVP infusion, suggesting that defects in osmotic NOMPC is present in sensory hair cells (49). Knockdown of regulation reside in central osmosensation, not in the kidney NOMPC in zebrafish impairs the acoustic startle reflex. tubules. OSM-9 and NOMPC are not present in mammals. Mamma- Varitint-waddler mice are spontaneously occurring mutant lian mechanosensitive TRP proteins include TRPV4, TRPP, mice characterized by deafness and circular behavior indicative and possibly TRPML3. As discussed above, TRPV4 is a mam- of vestibular dysfunction (54). Mutant mice show malian TRPV member that senses temperature, osmolarity, and degeneration in the first few weeks after birth. Positional other mechanical stimuli (16,71,72). Besides sensory neurons, cloning has recently identified Mcoln3 (TRPML3) as the gene TRPV4 is expressed in renal distal tubules, where interstitial mutated in varitint-waddler mice (54). TRPML3 localizes to osmolarity fluctuates markedly. TRPV4 is expressed in osmo- intracellular vesicles and plasma membrane of stereocilia in sensing circumventricular organs of brain, mechanosensitive Cochlea hair cells. The physiologic role of TRPML3 in hair heart and vascular endothelial cells, and mechanosensitive cells is unknown. However, its location in stereocilia raises an inner ear hair cells (16,71,72). TRPV4, however, is not essen- interesting possibility that it may function as a transduction tial for all of these functions. TRPV4Ϫ/Ϫ mice exhibit im- channel in hair cells. paired osmotic regulation and a reduced response to noxious PKD1 and PKD2 are TRPP proteins that likely play impor- mechanical stimuli but have no detectable defects in hearing tant roles in sensing fluid flow in renal tubules. PKD1 and and auditory responses and maintaining core body temperature PKD2 proteins (also called polycystin-1 and -2) both are lo- (76). TRPV4 knockout mice have a slightly higher serum calized in the apical of renal tubular epithelial cells J Am Soc Nephrol 15: 1690–1699, 2004 TRP Channels 1695

(77,78). Bending of the cilia in cultured epithelial cells by flow Role of TRP in Divalent Ion Homeostasis ϩ ϩ causes influx (79). Nauli et al. (80) recently reported (Re)absorption of Ca2 and Mg2 in kidney and intes- that the calcium response to bending is diminished in cells that tine is essential for homeostasis of these ions in the body. ϩ ϩ lack cilia, in cells that lack PKD1, or in cells that are treated Transepithelial transport of Ca2 and Mg2 in these tissues with a blocking to PKD2. These experiments suggest occurs via paracellular as well as transcellular routes. Trans- that PKD1 and PKD2 are involved in calcium influx activated cellular reabsorption of these ions, although accounting for a by flow-induced bending of the apical cilium. Defects in fluid smaller portion of the total reabsorption than paracellular route, flow sensation by cilia and Ca2ϩ influx likely play pivotal roles is the primary target for regulation by hormones and acid–base 2ϩ 2ϩ in cyst formation in kidney and other organs in polycystic disturbances. Transcellular reabsorption of Ca and Mg is kidney diseases. mediated by diffusion into cells through ion channels in the PKD proteins are also important in embryonic development. apical membrane followed by extrusion across basolateral membranes via pumps or exchangers. TRPV5 was initially The embryonic ventral node, which appears in the gastrulation identified as the apical Ca2ϩ entry channel in kidney and was stage of vertebrate development, consists of a dorsal layer of ϩ localized to the Ca2 -reabsorptive distal convoluted tubules ectoderm over a ventral layer of cells each containing a single (DCT) (17). TRPV6 was identified as the apical channel re- cilium. Normal left-right body asymmetry depends on a left- ϩ sponsible for intestinal absorption of Ca2 (18). Recent stud- ward nodal flow generated by ciliated nodal cells. McGrath et ies, however, have found that both TRPV5 and TRPV6 are al. (81) showed that there are two types of nodal cilia: one is expressed in the DCT of kidney, where they may form hetero- motile but does not contain PKD2, and the other is nonmotile multimers (89). TRPV6 is also expressed in medullary collect- but contains PKD2. The motile ciliated cells located in the ing ducts (90), where Ca2ϩ reabsorption is not known to take center of the node generate fluid flow that is sensed by non- place under physiologic conditions. The role of TRPV6 in this motile PKD2-containing ciliated cells in the peripheral region segment remains to be identified. Mice with targeted ablation 2ϩ of the node. Increase in cytosolic Ca in the left side of the of TRPV5 have been generated (91) and exhibit polyuria and node is thought to be important for establishing left-right hypercalciuria, providing support for an essential role of asymmetry. Homologues of PKD1 and PKD2 are also present TRPV5 in renal Ca2ϩ reabsorption. Consistent with the phe- in C. elegans (82,83), where they are located in ciliated mech- notype of renal Ca2ϩ wasting, TRPV5 knockout ex- anosensory neurons of male copulatory organs and in other hibit compensatory intestinal hyperabsorption of Ca2ϩ and ciliated . Together, these reports support the reduced bone thickness. important role of PKD proteins in ciliary mechanosensation. Increased acid load in conditions such as high dietary protein ϩ The identity of pore-forming protein(s) in PKD2-related intake and metabolic acidosis increases urinary Ca2 excretion channel activity remains unclear. Channel activity recorded (92). A recent study reported that extracellular bind to from PKD2 proteins reconstituted in is strongly a titratable amino acid, glutamate-522 (a “pH sensor”), in the voltage dependent: Open probability is higher at hyperpolar- extracellular loop of rabbit TRPV5 and inhibit its activity (93). ized membrane potentials and reduced to near zero at positive A similar titratable amino acid, histidine, is present in human membrane potentials (41,84). This voltage dependence of sin- TRPV6, which could mediate extracellular acid regulation of gle-channel open probability would predict a strongly inwardly TRPV5/6 heteromeric channels in the DCT. It has been esti- rectifying whole-cell current if PKD2 proteins were expressed mated that inhibition of TRPV5/6 caused by a decrease in on the surface membrane and solely contributed to membrane lumen pH from 6.8 to 6.4 would lead to doubling of urinary Ca2ϩ excretion (93). currents. However, expression of PKD2 with or without PKD1 Familial hypomagnesemia with secondary hypocalcemia is in cultured cells produces surface membrane whole-cell cur- an autosomal recessive disease characterized by renal wasting rents with nearly linear current–voltage relationships (85,86). It ϩ and defective intestinal absorption of Mg2 and secondary has been shown that PKD2 protein can physically associate hypocalcemia. Schlingmann et al. (31) and Walder et al. (32) with TRPC1 (40). The molecular composition of pore-forming reported that familial hypomagnesemia is caused by mutations protein(s) underlying the whole-cell currents in PKD2-express- of TRPM6. TRPM6 proteins are expressed in kidney and ing cells versus the single-channel activity recorded in lipid intestine, supporting the hypothesis that they are Mg2ϩ chan- bilayer deserves further investigation (87). nels responsible for Mg2ϩ transport in these tissues. Transcel- lular reabsorption of Mg2ϩ in kidney occurs in DCT. A recent paper reported that TRPM6 is localized to the apical membrane TRP as Taste Sensors of DCT in kidney and the brush border of the Salt and sour taste are detected by members of the DNG/ (94). Expression of TRPM6 in cultured HEK cells produces a ENaC superfamily. The ability of certain TRP proteins to Mg2ϩ-permeable channel that is regulated by intracellular integrate physical and chemical stimuli (e.g., TRPV4, OSM-9) Mg2ϩ (94). TRPM6 contains an atypical kinase domain in the suggests that TRP may play roles in the perception of taste. C-terminus (31,32). Indeed, it has been found that TRPM5 is expressed in taste TRPM7 is ~50% identical to TRPM6 and contains an atyp- buds. TRPM5 may be responsible for perception of bitter ical kinase domain as well (33,34). TRPM7 is ubiquitous and and/or sweet compounds (88). conducts divalent cations, including Mg2ϩ,Ca2ϩ, and trace 1696 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1690–1699, 2004 elements such as Mn2ϩ and Co2ϩ (95,96). Cultured cells in Kojima I, Mori Y, Penner R, Prawitt D, Scharenberg AM, which the TRPM7 gene has been inactivated have decreased Schultz G, Shimizu N, Zhu MX: A unified nomenclature for the viability, which can be rescued by supplementation of extra- superfamily of TRP cation channels. Mol Cell 92: 229–231, cellular Mg2ϩ (34,97). Mg2ϩ uptake through TRPM7 requires 2002 a functional coupling between its channel and kinase domain 5. Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, Montell C: TRPC1, a human homolog of a Drosophila store- (97). Chubanov et al. (98) reported that TRPM6 and TRPM7 operated channel. Proc Natl Acad SciUSA92: 9652–9656, interact with each other to increase channel currents in cultured 1995 HEK cells. 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