Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 57, Issue 4, Pages 407-415Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0b013e31820b7c03
Keywords
mefloquine; inward rectifier potassium channel; PIP2
Funding
- CONACYT-SEP (Mexico) [CB-2008-01-105941]
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The antimalarial drug mefloquine was found to inhibit the K-ATP channel by an unknown mechanism. Because mefloquine is a Cationic amphiphilic drug and is known to insert into lipid bilayers, we postulate that mefloquine interferes with the interaction between PIP2 and Kir channels resulting in channel inhibition. We studied the inhibitory effects of mefloquine on Kir2.1, Kir2.3, Kir2.3(I213L), and Kir6.2/SUR2A channels expressed in HEK-293 cells, and on I-K1 and I-KATP from feline cardiac myocytes. The order of mefloquine inhibition was Kir6.2/SUR2A approximate to Kir2.3 (IC50 approximate to 2 mu M) > Kir2.1 (IC50 > 30 mu M). Similar results were obtained in cardiac myocytes. The Kir2.3(I213L) mutant, which enhances the strength of interaction with PIP2 (compared to WT), was significantly less sensitive (IC50 = 9 mu M). In inside-out patches, continuous application of PIP2 strikingly prevented the mefloquine inhibition. Our results support the idea that mefloquine interferes with PIP2-Kir channels interactions.
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