An intelligent nano-antenna: Primary cilium harnesses TRP channels to decode polymodal stimuli

Abstract

The primary cilium is a solitary hair-like organelle on the cell surface that serves as an antenna sensing ever-changing environmental conditions. In this review, we will first recapitulate the molecular basis of the polymodal sensory function of the primary cilia, specifically focusing on transient receptor potential (TRP) channels that accumulate inside the organelle and conduct calcium ions (Ca(2+)). Each subfamily member, namely TRPP2 TRPP3, TRPC1 and TRPV4, is gated by multiple environmental factors, including chemical (receptor ligands, intracellular second messengers such as Ca(2+)), mechanical (fluid shear stress, hypo-osmotic swelling), or physical (temperature, voltage) stimuli. Both activity and heterodimer compositions of the TRP channels may be dynamically regulated for precise tuning to the varying dynamic ranges of the individual input stimuli. We will thus discuss the potential regulation of TRP channels by local second messengers. Despite its reported importance in embryonic patterning and tissue morphogenesis, the precise functional significance of the downstream Ca(2+) signals of the TRP channels remains unknown. We will close our review by featuring recent technological advances in visualizing and analyzing signal transduction inside the primary cilia, together with current perspectives illuminating the functional significance of intraciliary Ca(2+) signals.

Keywords: Cilium-targeted Ca(2+) indicators; Local Ca(2+)signals; Polymodal sensitivity; Primary cilium; TRPC1; TRPP2; TRPP3; TRPV4.

Figure 1

Primary cilium harbors diverse signaling components to serve its role as a polymodal sensory organelle. The intraflagellar transport (IFT) machinery is a cilium-specific trafficking machinery that regulates anterograde (IFT-B) and retrograde (IFT-A) transport within the cilium. RTK: receptor tyrosine kinase (EGFR: epithelial growth factor receptor; PDGFR-αα: platelet-derived growth factor receptor α homodimer; IGFR: insulin-like growth factor receptor); GPCR: G-protein coupled receptor (5HT6: serotonin receptor isoform 6; SSTR3: somatostatin receptor isoform 3; Smo: smoothened) AC III: adenylate cyclase class III; 5-ptase: phosphoinositide 5-phosphatase (INPP5e: inositol polyphosphate-5-phosphatase; OCRL: oculocerebrorenal syndrome of Lowe); CaM: Calmodulin.

Figure 2

Proposed cilium-specific regulation of ciliary TRP channels. (A) TRP channels from different sub-families could hetero-multimerize into ion channel assemblies of novel gating and regulatory properties within the primary cilium. (B) Ciliary TRP channels could serve as downstream effectors of receptors selectively concentrated within primary cilium, an example being via phospholipase C-β/γ, (C) Absence of actin cytoskeleton and actin-associated proteins within primary cilium could result in a dynamic organization of receptors and ion channels that is distinct from contiguous plasma membrane. (D) Enrichment of phosphoinositide 5-phosphatases within primary cilium could alter phosphatidylinositol composition of cilium membrane, modulating phosphatidylinositol-dependent regulation of TRP channel activity. (E) Intrinsic properties of kidney primary cilium could sensitize mechanosensitive ciliary TRP channels to shear stress caused by fluid flow within kidney tubule.