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1 Physiology, Chicago Medical School, North Chicago, Illinois, United States; Physiology, Gyeongsang National University, Jinju, Korea, Republic of
2 Physiology, Gyeongsang National University, Jinju, Korea, Republic of
3 Physiology, Chicago Medical School, North Chicago, Illinois, United States
* To whom correspondence should be addressed. E-mail: donghee.kim{at}rosalindfranklin.edu.
TREK-2 is a member of the two-pore domain K+ channel family, and provides part of the background K+ current in many types of cells. Neurotransmitters that act on receptors coupled to Gq strongly inhibit TREK-2 and thus enhance cell excitability. The molecular basis for the inhibition of TREK-2 was studied. In COS-7 cells expressing TREK-2 and M3 receptor, acetylcholine (ACh) applied to the bath solution strongly inhibited the whole-cell current, and this was markedly reduced in the presence of U73122, an inhibitor of PLC. The inhibition was also observed in cell-attached patches when ACh was applied to the bath solution. In inside-out patches, direct application of GTP
S (10 µM), Ca2+ (5 µM) or diacylglycerol (DAG, 10 µM) produced no inhibition of TREK-2 in more than 75% of patches tested. Phosphatidic acid, a product of DAG kinase, had no effect on TREK-2. Pretreatment of cells with 20 µM wortmannin, an inhibitor of phosphatidylinositol kinases, did not affect the inhibition or the recovery from inhibition of TREK-2, suggesting that phosphatidylinositol-4,5-bisphosphate (PIP2) depletion did not mediate the inhibition. Pretreatment of cells with a protein kinase C inhibitor (bisindolylmaleimide, 10 µM) markedly inhibited ACh-induced inhibition of TREK-2. Mutation of two putative PKC sites (S326A, S359C) abolished inhibition by ACh. Mutation of these amino acids to aspartate to mimic the phosphorylated state resulted in diminished TREK-2 current and no inhibition by ACh. These results suggest that the agonist-induced inhibition of TREK-2 via M3 receptor occurs primarily via PKC-mediated phosphorylation.
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