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 critical 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.

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).…”

Gates for soluble and membrane proteins, and two trafficking systems (IFT and LIFT), establish a dynamic ciliary signaling compartment

“…As regulatable cellular antenna, cilia concentrate signaling proteins within the organelle (e.g., cGMP/ cAMP signal transduction components), or spatially separate, over a small distance, different components of the same signalling pathway (e.g., Hedgehog, Insulin/IGF and TGF-b pathways) [17,18,27] (Figure 1). …”

Endocytic Control of Cellular Signaling at the Primary Cilium

“…A large body of evidence has substantiated their importance as coordinators of many developmentally and physiologically relevant signaling pathways, including Shh [1,2], Wingless/int (Wnt) [3], Notch [4], receptor tyrosine kinase (RTK) [5], and TGF-b signaling [6], as well as signaling through extracellular matrix (ECM) receptors [7], GPCRs [8,9], purinergic receptors [10], and ion channels [11].…”