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G-Protein-Coupled Receptor Signaling in Cilia

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G-Protein-Coupled Receptor Signaling in Cilia Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press G-Protein-Coupled Receptor Signaling in Cilia Kirk Mykytyn1,2 and Candice Askwith2,3 1Department of Biological Chemistry and Pharmacology, The Ohio State University, Ohio 43210 2Neuroscience Research Institute, The Ohio State University, Ohio 43210 3Department of Neuroscience, The Ohio State University, Ohio 43210 Correspondence: [email protected] G-protein-coupled receptors (GPCRs) are the largest and most versatile family of signaling receptors in humans. They respond to diverse external signals, such as photons, proteins, peptides, chemicals, hormones, lipids, and sugars, and mediate a myriad of functions in the human body. Signaling through GPCRs can be optimized by enriching receptors and down- stream effectors in discrete cellular domains. Many GPCRs have been found to be selectively targeted to cilia on numerous mammalian cell types. Moreover, investigations into the path- ophysiology of human ciliopathies have implicated GPCR ciliary signaling in a number of developmental and cellular pathways. Thus, cilia are now appreciated as an increasingly important nexus for GPCR signaling. Yet, we are just beginning to understand the precise signaling pathways mediated by most ciliary GPCRs and how they impact cellular function and mammalian physiology. t is estimated that the human genome encodes In canonical GPCR signaling at the plas- Iapproximately 950 G-protein-coupled recep- ma membrane, agonist binding to a receptor tors (GPCRs), of which 500 correspond to causes a change in receptor conformation and odorant or taste receptors (Takeda et al. 2002). results in activation of heterotrimeric GTP- Approximately 150 of the remaining 450 binding proteins (G proteins) (Fig. 1A) (She- GPCRs have no known natural ligand and so noy and Lefkowitz 2011). G proteins consist are referred to as orphan GPCRs (Tang et al. of three associated protein subunits: a, b, and 2012). GPCRs represent the largest group of g. G proteins are classified based on the na- therapeutic drug targets, with more than a third ture of their a-subunits and there are 16 of all drugs acting on GPCRs (Rask-Andersen known a-subunits that are functionally cate- et al. 2011). Because of the functional diversity gorized into four subfamilies: Gas,Gai,Gaq, of GPCRs, there is little conservation of amino and Ga12. When inactive, the a-subunit is acid sequence across the GPCR superfamily. bound to GDP and a bg-complex to form a Yet, all GPCRs share a common structure: an trimeric protein complex (Fig. 1A). On ago- extracellular amino terminus, seven transmem- nist binding, the receptor facilitates GDP re- brane domains, and an intracellular carboxyl lease, GTP binding to the a-subunit, and dis- terminus. sociation of the a-subunit from the bg- Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028183 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028183 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press K. Mykytyn and C. Askwith A Ligand N N GPCR C GTP C GDP Gγ Gα Gβ α G Gγ Gβ i/o S 12/13 T q Ion channels Numerous other effectors Adenylyl RHO/GEFs cyclase Phospholipases (inhibition) Phosphodiesterase Adenylyl cyclase (stimulation) B N Activated GPCR C GRK β-Arrestin G-protein-independent signaling ERK, MAPK, Src, JNK, REF, many others Internalization, desensitization, and/or endosomal signaling Figure 1. Overview of G-protein-coupled receptor (GPCR) signaling at the plasma membrane. (A) Ligand binding to a GPCR facilitates GDP release from the G-protein a-subunit and stimulates GTP binding to the a-subunit, which leads to dissociation of the a-subunit from the bg-complex. Both the a-subunit and bg- complex can then regulate various intracellular effectors. (B) Activated GPCRs are phosphorylated at specific sites on their intracellular domains predominantly by G-protein-coupled receptor kinases (GRKs). Phosphor- ylated receptors are targets for the recruitment of b-arrestins, which prevent further G-protein activation and mediate internalization of receptors by promoting clathrin-mediated endocytosis. b-Arrestins bind to numer- ous intracellular signaling proteins and can act as signal transducers independently of G-protein coupling. In some cases, GPCR signaling can be sustained or enhanced on endocytosis. 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028183 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Ciliary GPCR Signaling complex (Fig. 1A). Both the a-subunit and OLFACTORY RECEPTOR SIGNALING bg-complex can then regulate various intra- cellular effectors (e.g., adenylyl cyclases by the Ciliopathies can be associated with deficits in a-subunit and potassium channels by the bg- olfaction (Kulaga et al. 2004; Iannaccone et al. complex). 2005; McEwen et al. 2007). Mammalian olfac- Activated GPCRs are then phosphorylated tion is mediated by olfactory sensory neurons at specific sites on their intracellular domains (OSNs) that project from the olfactory bulb in predominantly by G-protein-coupled receptor the brain to the olfactory epithelium located in kinases (GRKs) (Fig. 1B) (Marchese et al. 2008), the nasal cavity (Fig. 3A). OSNs are bipolar but also other kinases such as protein kinase A neurons with a single axon that projects distally (PKA) or protein kinase C (PKC) (Kelly et al. to the olfactory bulb and a single dendrite that 2008). Once phosphorylated, the receptors be- projects apically to the olfactory epithelium. At come targets for the recruitment and binding the apical end of the OSN, the dendritic tip is of scaffolding proteins, termed b-arrestins, enlarged to form a dendritic knob from which which prevent further G-protein activation and 10 to 30 nonmotile 9þ2 cilia project (Menco mediate internalization of receptors by pro- 1980, 1997). These olfactory cilia range from 50 moting clathrin-mediated endocytosis (Fig. to 60 mm in length and extend into the olfactory 1B) (Shenoy and Lefkowitz 2011). This pro- mucus where they are directly exposed to odor- cess is known as homologous desensitization. ants (Jenkins et al. 2009). There are two impor- Although internalization of GPCRs is gener- tant consequences of the ciliary structure. First, ally associated with a decrease in signaling, the presence of numerous cilia increases the in some cases receptor signaling can be sus- surface area that is exposed to the external en- tained or enhanced on endocytosis (Sorkin vironment by about 40 times and enhances our and von Zastrow 2009; McMahon and Boucrot ability to detect odorants (Menco 1992). Sec- 2011). In addition, b-arrestins bind to numer- ond, the small diameter of the distal ends of ous intracellular signaling proteins, includ- these cilia (0.1 mm) leads to a large ratio of ing Src, ERK1/2, p38, and PI3K, and can act membrane surface area to cytoplasmic volume as signal transducers independent of G-protein (Menco 1980), allowing a small signal to gener- coupling (DeFea 2011; Shukla et al. 2011). ate a large effect. There are two b-arrestin isoforms (1 and 2) that The molecular elements required for olfac- are expressed ubiquitously and regulate most tory transduction are concentrated within the GPCRs. ciliary compartment (Fig. 3B). Olfaction be- There is an ever-expanding list of GPCRs gins with binding of an odorant to an olfactory that are enriched in cilia on a variety of cell types receptor (OR) on the ciliary membrane. In ro- (Table 1; Fig. 2). Numerous GPCR effector mol- dents, each OSN predominantly expresses one ecules have also been localized to cilia (Fig. 2) of approximately 1000 ORs (Ressler et al. 1993; (Hilgendorf et al. 2016), suggesting that cilia Vassar et al. 1993), which triggers the activation mediate signaling of a diverse set of GPCRs. of the heterotrimeric stimulatory G protein Importantly, ciliopathies are associated with al- comprising Gaolf, b1, and g13 (Jones and terations in GPCR signaling. In this review, we Reed 1989; Kerr et al. 2008; Li et al. 2013). will focus on mammalian cilia-mediated GPCR Gaolf then activates type 3 adenylyl cyclase signaling transduction pathways. We will begin (AC3), which increases cAMP levels within with a brief account of the well-described sig- the cilium (Bakalyar and Reed 1990). The naling pathways mediated by the prototypical cAMP then binds to and activates cyclic-nucle- ciliary GPCRs, odorant receptors, and opsins. otide-gated (CNG) channels on the ciliary Then we will discuss more recently described membrane, allowing the entry of calcium ions examples of GPCR ciliary signaling with a focus and depolarizing the membrane potential. In- on the potential functional impacts of cilia on creased ciliary Ca2þ levels leads to activation GPCR signaling. and opening of Ca2þ-gated chloride channels, Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028183 3 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press K. Mykytyn and C. Askwith Table 1. Nonodorant/nonvisual G-protein-coupled receptors (GPCRs) with confirmed ciliary localization GPCR Cell type References b2-adrenergic receptor (b2AR) Neurons Yao et al. 2015 Bile acid receptor (TGR5) Cholangiocytes Keitel et al. 2010; Masyuk et al. 2013 Bitter taste receptors (T2R) Airway epithelial cells Shah et al. 2009 Dopamine receptor 1 (D1) Neurons Domire et al. 2011 Dopamine receptor 5 (D5) Vascular endothelial cells, Abdul-Majeed and Nauli 2011; renal epithelial cells Jin et al. 2014b Galanin receptor 3 (GALR3) Neurons Loktev and Jackson 2013 GPR83 Neurons Loktev and Jackson 2013 GPR161 Neurons, mouse embryonic Mukhopadhyay et al. 2013 fibroblasts GPR175 Mouse embryonic Singh et al. 2015 fibroblasts Kisspeptin receptor 1 (KISS1R) Neurons Koemeter-Cox et al.
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