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Cells 2014, 3(2), 247-257;

PKC-dependent Phosphorylation of the H1 Histamine Receptor Modulates TRPC6 Activity

Indiana University School of Medicine, 635 Barnhill Dr., MS360A, Indianapolis, IN 46202, USA
Montana Molecular, Bozeman, MT 59715, USA
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Author to whom correspondence should be addressed.
Received: 18 February 2014 / Revised: 17 March 2014 / Accepted: 25 March 2014 / Published: 4 April 2014
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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Transient receptor potential canonical 6 (TRPC6) is a cation selective, DAG-regulated, Ca2+-permeable channel activated by the agonists of Gq-protein-coupled heptahelical receptors. Dysfunctions of TRPC6 are implicated in the pathogenesis of various cardiovascular and kidney conditions such as vasospasm and glomerulosclerosis. When stimulated by agonists of the histamine H1 receptor (H1R), TRPC6 activity decays to the baseline despite the continuous presence of the agonist. In this study, we examined whether H1R desensitization contributes to regulating the decay rate of TRPC6 activity upon receptor stimulation. We employed the HEK expression system and a biosensor allowing us to simultaneously detect the changes in intracellular diacylglycerol (DAG) and Ca2+ concentrations. We found that the histamine-induced DAG response was biphasic, in which a transient peak was followed by maintained elevated plateau, suggesting that desensitization of H1R takes place in the presence of histamine. The application of PKC inhibitor Gö6983 slowed the decay rate of intracellular DAG concentration. Activation of the mouse H1R mutant lacking a putative PKC phosphorylation site, Ser399, responsible for the receptor desensitization, resulted in a prolonged intracellular DAG increase and greater Mn2+ influx through the TRPC6 channel. Thus, our data support the hypothesis that PKC-dependent H1R phosphorylation leads to a reduced production of intracellular DAG that contributes to TRPC6 activity regulation. View Full-Text
Keywords: TRPC6; desensitization; DAG; PKC; H1 receptor TRPC6; desensitization; DAG; PKC; H1 receptor

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Chen, X.; Egly, C.; Riley, A.M.; Li, W.; Tewson, P.; Hughes, T.E.; Quinn, A.M.; Obukhov, A.G. PKC-dependent Phosphorylation of the H1 Histamine Receptor Modulates TRPC6 Activity. Cells 2014, 3, 247-257.

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