Protein kinase C‐mediated Ca²⁺ entry in HEK 293 cells transiently expressing human TRPV4

Abstract

increase with a different latency, while 4a-phorbol had no effect. 4 The PMA-induced [Ca 2 þ ] i increase was abolished by prior exposure to bisindolylmaleimide (BIM), a PKC-specific inhibitor, and suppressed by the nonspecific PKC inhibitor 1-(5-isoquinolinesulphonyl)-2-methylpiperazine. The [Ca 2 þ ] i increase induced by 4a-PMA, 4a-PDD or HTS was not significantly affected by BIM. 5 These results suggest that both PKC-dependent and -independent mechanisms are involved in the phorbol ester-induced activation of TRPV4, and the PKC-independent pathway is predominant in HTS-induced Ca 2 þ entry.

TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

“…Interestingly, other 4␣-phorbol isomers positively modulate CBF through PKC phosphorylation (32). The facts that 4␣PDD binds and activates TRPV4 (17) without the involvement of PKC (16) and that the response to 4␣PDD is totally lost in different TRPV4 Ϫ/Ϫ cells (ref. 29 and this study) strongly suggest that the 4␣PDD effects are mainly TRPV4-mediated, although we cannot completely rule out the participation of other pathways.…”

“…The TRPV4 cation channel, a member of the TRP vanilloid subfamily, responds to a range of stimuli, including osmotic cell swelling, mechanical stress, temperature, endogenous arachidonic acid metabolites, and phorbol esters (15,16). As a result, 4␣-phorbol 12,13-didecanoate (4␣PDD) has become a valuable pharmacological tool to functionally test TRPV4 activity, because 4␣PDD interacts directly with transmembrane domains 3 and 4 of TRPV4 (17).…”

IP3 Receptor Binds to and Sensitizes TRPV4 Channel to Osmotic Stimuli via a Calmodulin-binding Site

“…TRPV4 participation in osmo-and mechanotransduction (1, 2) contributes to important functions including cellular (3, 4) and systemic volume homeostasis (5, 6), arterial dilation (7,8), nociception (9), epithelial hydroelectrolyte transport (10, 11), bladder voiding (12), and ciliary beat frequency regulation (13)(14)(15). TRPV4 also responds to temperature (16,17), endogenous arachidonic acid (AA) metabolites (18), and phorbol esters including the inactive 4␣-phorbol 12,13-didecanoate (4␣PDD) (19,20) and participates in receptor-operated Ca 2ϩ entry (15), thus showing multiple modes of activation.TRPV4 channel activity can be sensitized by co-application of different stimuli (9,21,22) or participation of different cell signaling pathways (14), suggesting the presence of different regulatory sites. In this sense, several proteins have been proposed to modulate TRPV4 subcellular localization and/or function: microtubuleassociated protein 7 (23), calmodulin (CaM, (24)), with no lysine protein kinases (25), and PACSIN3 (26).…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…Two transduction pathways have been proposed to regulate TRPV4 activation: the phospholipase (PL) C (PLC)/diacylglycerol (DAG) pathway and the PLA 2 /arachidonic acid (AA) pathway [96,97]. Some evidence suggests that activation of TRPV4 by hypotonicity involves its phosphorylation by the Src family of tyrosine kinase [98]. Although the molecular mechanism of hypotonicity-induced TRPV4 activation should be further investigated, studies addressing the gating mechanism of the channel by cell swelling exclude that it is directly gated by mechanotransduction since it does not respond to membrane stretch [90].…”

“…Tyrosine kinases are known to regulate trafficking of ion channels and receptors. Recent reports demonstrate that Src tyrosine kinases participate in the modulation of TRP channel function [98,104,105], and this mechanism could be responsible for TRPV4 sensitization. In paclitaxel-induced peripheral neuropathy TRPV4-mediated mechanical hyperalgesia results essentially dependent on integrin/Src tyrosine kinase signaling [101].…”