Academic journal article Genetics

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis Elegans Sensory Cilia

Academic journal article Genetics

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis Elegans Sensory Cilia

Article excerpt

SIGNALING molecules must be precisely localized to spe- cific subcellular domains to optimize detection and trans- duction of external stimuli. G protein-coupled receptors (GPCRs) comprise a large family of transmembrane signaling proteins that directly bind and transduce a range of cues including photons, odorants, neurotransmitters, and pepti- des (Pierce et al. 2002; Kato and Touhara 2009; Demaria and Ngai 2010; Sung and Chuang 2010; Chamero et al. 2012; Frooninckx et al. 2012; Montell 2012; Bathgate et al. 2013). Regulation of GPCR function, including regu- lation of membrane targeting and trafficking to specific sub- cellular regions, is a major contributor to the tuning of signaling efficacy and fidelity (e.g., Deretic et al. 1995; Dwyer et al. 1998; Ango et al. 2000; Xia et al. 2003; Esseltine et al. 2012; Loktev and Jackson 2013). However, much remains to be understood regarding the mechanisms by which GPCR trafficking and membrane localization are regulated.

GPCR-mediated signal transduction in many cellular contexts requires these proteins to be localized to special- ized microtubule-based primary cilia. For example, in photoreceptors and olfactory neurons, efficient sensory signal transduction is mediated via localization of rhodopsin and olfactory receptors, together with other signaling molecules, to photoreceptor outer segments and olfactory neuron cilia, respectively (Insinna and Besharse 2008; Berbari et al. 2009; Pifferi et al. 2010; Deretic and Wang 2012). Receptors in the Hedgehog (Hh) morphogen signaling path- way such as the Smoothened and Patched transmembrane proteins, and the Gpr161 putative GPCR, are dynamically localized in the cilium as a function of the presence or ab- sence of the Hh cue; failure to correctly localize these recep- tors results in altered Hh signaling and severe developmental consequences (Goetz et al. 2009; Mukhopadhyay et al. 2013; Nozawa et al. 2013). However, within a given cell type, closely related members of a GPCR family can be differentially targeted to different cell compartment mem- branes. For instance, in mammalian neurons, only the so- matostatin receptor subtype 3 (Sstr3) GPCR is localized to cilia, whereas the five related Sstr GPCRs are instead tar- geted to membranes of neuronal soma, axons, or dendrites (Handel et al. 1999; Schulz et al. 2000; Berbari et al. 2008a). Thus, ciliary localization of GPCRs is tightly regu- lated as a function of cell type, signaling conditions, as well as GPCR identity.

Mechanisms required for GPCR targeting to cilia have been studied intensively. Ciliary GPCRs contain sequences (termed ciliary targeting sequences, CTSs) that are recog- nized by specific adaptor proteins that promote trafficking to cilia (Rosenbaum and Witman 2002; Pazour and Blood- good 2008; Emmer et al. 2010; Nachury et al. 2010; Loktev and Jackson 2013; Sung and Leroux 2013). Both CTSs and the required adaptor proteins are quite diverse. Sequences in the third intracellular loop, as well as in the C-terminal tail, have been implicated in ciliary targeting of individual GPCRs (Deretic et al. 1998; Tam et al. 2000; Dwyer et al. 2001; Corbit et al. 2005; Berbari et al. 2008a; Loktev and Jackson 2013; Mukhopadhyay et al. 2013). Similarly, mul- tiple trafficking mechanisms including vesicle-mediated transport and lateral diffusion both to and within the cil- iumhavebeenshowntoplayaroleinregulatingciliary GPCR composition in different cell types (Pazour and Bloodgood 2008; Emmer et al. 2010; Nachury et al. 2010; Ye et al. 2013; Sung and Leroux 2013). These results imply that GPCR trafficking may employ both protein- and cell-specific mechanisms. Thus, a detailed analysis of GPCR ciliary trafficking within and across defined cell types in vivo may greatly inform our knowledge of the underlying pathways.

GPCR-mediated signaling also plays a critical role in the lifecycle of Caenorhabditis elegans. As in the corresponding mammalian chemosensory cells, GPCRs required for sensory signaling are concentrated in cilia present at the dendritic endings of a subset of sensory neurons in C. …

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