TY - JOUR
T1 - Carbamazepine inhibits ATP-sensitive potassium channel activity by disrupting channel response to MgADP
AU - Zhou, Qing
AU - Chen, Pei Chun
AU - Devaraneni, Prasanna K.
AU - Martin, Gregory M.
AU - Olson, Erik M.
AU - Shyng, Show Ling
N1 - Funding Information:
This work was supported by the NIH grants DK057699 and DK066485 (to S.L.S.). G.M. is supported by an NIH Ruth L. Kirschstein T32 PMCB Training Grant.
PY - 2014
Y1 - 2014
N2 - In pancreatic β-cells, KATP channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion. Sulfonylureas, insulin secretagogues used to treat type II diabetes, inhibit KATP channel activity primarily by abolishing the stimulatory effect of MgADP endowed by SUR1. In addition, sulfonylureas have been shown to function as pharmacological chaperones to correct channel biogenesis and trafficking defects. Recently, we reported that carbamazepine, an anticonvulsant known to inhibit voltage-gated sodium channels, has profound effects on K ATP channels. Like sulfonylureas, carbamazepine corrects trafficking defects in channels bearing mutations in the first transmembrane domain of SUR1. Moreover, carbamazepine inhibits the activity of KATP channels such that rescued mutant channels are unable to open when the intracellular ATP/ADP ratio is lowered by metabolic inhibition. Here, we investigated the mechanism by which carbamazepine inhibits KATP channel activity. We show that carbamazepine specifically blocks channel response to MgADP. This gating effect resembles that of sulfonylureas. Our results reveal striking similarities between carbamazepine and sulfonylureas in their effects on KATP channel biogenesis and gating and suggest that the 2 classes of drugs may act via a converging mechanism.
AB - In pancreatic β-cells, KATP channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion. Sulfonylureas, insulin secretagogues used to treat type II diabetes, inhibit KATP channel activity primarily by abolishing the stimulatory effect of MgADP endowed by SUR1. In addition, sulfonylureas have been shown to function as pharmacological chaperones to correct channel biogenesis and trafficking defects. Recently, we reported that carbamazepine, an anticonvulsant known to inhibit voltage-gated sodium channels, has profound effects on K ATP channels. Like sulfonylureas, carbamazepine corrects trafficking defects in channels bearing mutations in the first transmembrane domain of SUR1. Moreover, carbamazepine inhibits the activity of KATP channels such that rescued mutant channels are unable to open when the intracellular ATP/ADP ratio is lowered by metabolic inhibition. Here, we investigated the mechanism by which carbamazepine inhibits KATP channel activity. We show that carbamazepine specifically blocks channel response to MgADP. This gating effect resembles that of sulfonylureas. Our results reveal striking similarities between carbamazepine and sulfonylureas in their effects on KATP channel biogenesis and gating and suggest that the 2 classes of drugs may act via a converging mechanism.
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U2 - 10.4161/chan.29117
DO - 10.4161/chan.29117
M3 - Article
C2 - 24849284
AN - SCOPUS:84905829301
SN - 1933-6950
VL - 8
SP - 376
EP - 382
JO - Channels
JF - Channels
IS - 4
ER -