An update on regulation of the polymodal TRPV4 channel by protein phosphorylation

TRPV4 is a polymodal Ca²⁺-permeable cation channel activated by diverse stimuli via various pathways and has been one of the difficult membrane proteins to comprehend, like other TRP channels. However, a broad range of functions and pathological conditions associated with these channels continues to fascinate researchers to study them. One of the major regulatory pathways of these channels is through protein phosphorylation catalyzed by various kinases (e.g. PKC, PKA, SGK1, and Src kinase) in a stimulus-specific manner. Several sites of protein phosphorylation have been identified in both N- and C-terminal tails located in the cytosolic region of the channel. One critical phosphorylation-mediated regulatory pathway involves the C-terminal phosphorylation of Ser-824 residue, which has been implicated in activation/sensitization of the channel and its functioning in cells. Due to the lack of structural evidence on the N- and C-terminal tails (largely intrinsically disordered), it remains a challenge to understand the molecular mechanisms involved in their regulation of the TRPV4 channel. However, recent studies have provided new insights into the potential mechanisms of phosphorylation regulation of the channel and helped unravel the complexity of TRPV4 regulation pathways. This review provides an updated summary of the regulatory role of post-translational regulation through phosphorylation, the kinases and residues involved in phosphorylation of the TRPV4 channel. Furthermore, we discuss the importance and potential mechanisms of the C-terminal domain, harboring the Ser-824 residue, in the regulation of channel activation and proper functioning.