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Transient receptor potential vanilloid 4 (TRPV4) activation by arachidonic acid requires protein kinase A-mediated phosphorylation. J Biol Chem 2018 04 06;293(14):5307-5322



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Pubmed Central ID




Scopus ID

2-s2.0-85045077479   11 Citations


Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable channel of the transient receptor potential (TRP) superfamily activated by diverse stimuli, including warm temperature, mechanical forces, and lipid mediators such as arachidonic acid (AA) and its metabolites. This activation is tightly regulated by protein phosphorylation carried out by various serine/threonine or tyrosine kinases. It remains poorly understood how phosphorylation differentially regulates TRPV4 activation in response to different stimuli. We investigated how TRPV4 activation by AA, an important signaling process in the dilation of coronary arterioles, is affected by protein kinase A (PKA)-mediated phosphorylation at Ser-824. Wildtype and mutant TRPV4 channels were expressed in human coronary artery endothelial cells (HCAECs). AA-induced TRPV4 activation was blunted in the S824A mutant but was enhanced in the phosphomimetic S824E mutant, whereas the channel activation by the synthetic agonist GSK1016790A was not affected. The low level of basal phosphorylation at Ser-824 was robustly increased by the redox signaling molecule hydrogen peroxide (H2O2). The H2O2-induced phosphorylation was accompanied by an enhanced channel activation by AA, and this enhanced response was largely abolished by PKA inhibition or S824A mutation. We further identified a potential structural context dependence of Ser-824 phosphorylation-mediated TRPV4 regulation involving an interplay between AA binding and the possible phosphorylation-induced rearrangements of the C-terminal helix bearing Ser-824. These results provide insight into how phosphorylation specifically regulates TRPV4 activation. Redox-mediated TRPV4 phosphorylation may contribute to pathologies associated with enhanced TRPV4 activity in endothelial and other systems.

Author List

Cao S, Anishkin A, Zinkevich NS, Nishijima Y, Korishettar A, Wang Z, Fang J, Wilcox DA, Zhang DX


David A. Wilcox PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Arachidonic Acid
Calcium Channels
Cells, Cultured
Coronary Vessels
Crystallography, X-Ray
Cyclic AMP-Dependent Protein Kinases
Endothelial Cells
Hydrogen Peroxide
Signal Transduction
TRPV Cation Channels
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a