Ins and outs of GPCR signaling in primary cilia

Abstract

Primary cilia are specialized microtubule-based signaling organelles that convey extracellular signals into a cellular response in most vertebrate cell types. The physiological significance of primary cilia is underscored by the fact that defects in assembly or function of these organelles lead to a range of severe diseases and developmental disorders. In most cell types of the human body, signaling by primary cilia involves different G protein-coupled receptors (GPCRs), which transmit specific signals to the cell through G proteins to regulate diverse cellular and physiological events. Here, we provide an overview of GPCR signaling in primary cilia, with main focus on the rhodopsin-like (class A) and the smoothened/frizzled (class F) GPCRs. We describe how such receptors dynamically traffic into and out of the ciliary compartment and how they interact with other classes of ciliary GPCRs, such as class B receptors, to control ciliary function and various physiological and behavioral processes. Finally, we discuss future avenues for developing GPCR-targeted drug strategies for the treatment of ciliopathies.

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…This was an unexpected localization for polycystic disease gene products since most fibrocystic diseases of the kidney and liver, including ADPKD, are associated with proteins that function in primary cilia (14). Primary cilia are minute solitary membraneenclosed micro tubule-based projections that serve as organelles integrating cellular sensory signals on the apical surface of many cell types, including bile duct and kidney tubule epithelial cells (15)(16)(17). Mutations in another noncilial protein, LDL receptorrelated protein 5 (LRP5), a coreceptor in canonical Wnt signaling, have also been implicated as causing PCLD (18).…”

Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites

“…Expression of other receptors that occasionally traffic to primary cilia, like type 1 dopamine receptors, have also been associated with increased cilia length (Avasthi et al, 2012;Schou et al, 2015).…”

“…This difference could have led to differences in responsiveness to pharmacological manipulation at the time of drug treatment on DIV9. Finally, intense overexpression of cilia-targeted receptors may alter the biology of cilia in unpredictable manners, especially since trafficking of GPCRs in and out of the primary cilium involves a complex interaction between intraflagellar transport complexes, "BBsome" proteins that are involved in complex network of interacting proteins that continues to be elucidated (Schou et al, 2015;Ye et al, 2017).…”

The Arf GEF GBF1 and Arf4 synergize with the sensory receptor cargo, rhodopsin, to regulate ciliary membrane trafficking

“…Through the control of lipid metabolism and the recruitment of canonical coat complexes and protein adaptors that recognize and sequester the appropriate membrane cargo, Arf GTPases play a central role in key processes such as the maintenance of the Golgi architecture, progression of cargo through the Golgi complex, as well as the Golgi-to-plasma-membrane targeting that is responsible for the delivery of sensory receptors and their associated complexes to primary cilia (Deretic, 2013;Donaldson and Jackson, 2011;Ezratty et al, 2016;Hilgendorf et al, 2016;Humbert et al, 2012;Schou et al, 2015;Schwarz et al, 2012;Wang and Deretic, 2014;Wright et al, 2011). The distal ciliary membrane of vertebrate retinal rod photoreceptor cells elaborates a unique sensory organelle, the rod outer segment (ROS), which is filled with several thousand membranous disks containing as many as a billion copies of the light receptor rhodopsin (Besharse, 1986).…”