The primary cilium as a cellular receiver: organizing ciliary GPCR signaling

Abstract

The primary cilium is an antenna-like cellular protrusion mediating sensory and neuroendocrine signaling. Its localization within tissue architecture and a growing list of cilia-localized receptors, in particular G-protein-coupled receptors, determine a host of crucial physiologies, which are disrupted in human ciliopathies. Here, we discuss recent advances in the identification and characterization of ciliary signaling components and pathways. Recent studies have highlighted the unique signaling environment of the primary cilium and we are just beginning to understand how this design allows for highly amplified and regulated signaling.

Figure 1. Schematic of the Primary Cilium

The cilium is comprised of the ciliary membrane surrounding the microtubule-based axoneme, which is nucleated by the basal body. The ciliary membrane is highly enriched for receptors, including GPCRs. These ciliary signaling components are transported to the base of the cilium along microtubules by the minus-end directed motor dynein, where they cross the transition zone to enter the cilium. Within the primary cilium, IFT-B and IFT-A couple to kinesin and dynein motors, respectively, for anterograde and retrograde transport of signaling components. DA refers to distal appendage.

Figure 2. Signaling in primary cilia

A) Schematic of ciliary Hedgehog signaling. In the absence of Sonic Hedgehog (Shh), Patched1 and Gpr161 are ciliary resulting in activation of PKA and processing of Gli transcription factors to a repressor form. In the presence of Shh, Patched1 and GPR161 exit the cilium allowing for ciliary entry of Smoothed (Smo), release of Gli and its translocation to the nucleus to activate hedgehog target genes B) Schematic of ciliary GPCR trafficking. The ciliary membrane contains a large repertoire of GPCRs. Trafficking of a subset of these is regulated by the BBSome and/or Tulp3. A subset of myristoylated (including transducin_α) and farnesylated proteins are bound by Unc119 and Pde6d, respectively, in the cytoplasm for targeting to the cilium. Once in the cilium, the lipidated cargo-carrier complex is bound by the small GTPase Arl3_GTP to result in release of the cargo. The Arl3 GEF, Arl13b, is exclusively ciliary. The coupling between GPCRs and specific G proteins or other effectors is poorly understood, but GPCRs typically have guanine nucleotide exchange factor activity for Gα subunits.