TRPV4 plays an evolutionary conserved role in the transduction of osmotic and mechanical stimuli in live animals

Abstract

The TRPV4 ion channel, previously named vanilloid receptor-related osmotically activated channel (VR-OAC), functions in vivo in the transduction of osmotic and mechanical stimuli. In trpv4 null mice, TRPV4 was found to be necessary for the maintenance of systemic osmotic equilibrium, and for normal thresholds in response to noxious mechanical stimuli. In a Caenorhabditis elegans TRPV mutant transgenic for mammalian TRPV4, the mammalian transgene was directing the osmotic and mechanical avoidance response in the context of the ASH 'nociceptive' neurone. Molecular mechanisms of gating of TRPV4 in vivo are not known at this point and have to be determined.

Figure 1. Schematic drawings showing the specifics of signal transduction in sensory (nerve) cells in response to odorant (A), osmotic (B–C) and mechanical (D–E) stimuli

A, the odorant activates the TRPV ion channel via a G protein-coupled receptor mechanism. This happens, e.g. in the ASH sensory neurone of C. elegans in response to 8-octanone, an aversive odorant. The TRPV channel, OSM-9 or OCR-2, is down-stream of the G protein-coupled receptor. Calcium influx through the TRPV channel is an amplification mechanism which is necessary for this signalling pathway. B, one hypothetical scenario where, analogous to A, the TRPV channel functions down-stream of an – as yet unknown – osmotic stimulus transduction apparatus. Intracellular signalling via phosphorylation (dephosphorylation)-dependent pathways activates the channel. For heterologous cellular expression systems, two groups have obtained – contradictory – data that suggest phosphorylation of TRPV4 to be of relevance (Vriens et al. 2003; Xu et al. 2003). C, another hypothetical scenario where the TRPV channel is on top of the signalling cascade. Scenario I and II need not be mutually exclusive. Apart from phosphorylation of the TRPV channel, which could possibly be of relevance in vivo, a direct physical linkage of the TRPV channel to the cytoskeleton, to the extracellular matrix and to the lipids of the plasma membrane adjacent to the channel has to be considered. D, a hypothetical scenario re mechanotransduction. Here, an unknown mechanotransduction channel responds to the mechanical stimulus with calcium influx. This activity and the subsequent signal transduction are modulated by the TRPV channel. E, another hypothetical scenario re mechanotransduction. Here, the TRPV channel is the mechanotransducer itself. The data that we have obtained suggest the scenarios in C and E, whereas what happens in A does not happen when the OSM-9 channel is replaced with TRPV4 (Liedtke et al. 2003).