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CELLULAR AND MOLECULAR

Potent Inhibition of Native TREK-1 K⁺ Channels by Selected Dihydropyridine Ca²⁺ Channel Antagonists

Department of Neuroscience, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio

Bovine adrenal zona fasciculata (AZF) cells express bTREK-1 background K⁺ channels that set the resting membrane potential. Whole-cell and single-channel patch-clamp recording were used to compare five Ca²⁺ channel antagonists with respect to their potency as inhibitors of native bTREK-1 K⁺ channels. The dihydropyridine (DHP) Ca²⁺ channel antagonists amlodipine and niguldipine potently and specifically inhibited bTREK-1 with IC₅₀ values of 0.43 and 0.75 µM, respectively. The other Ca²⁺ channel antagonists, including the DHP nifedipine, the diphenyldiperazine flunarizine, and the cannabinoid anandamide were less potent, with IC₅₀ values of 8.18, 2.48, and 5.07 µM, respectively. Additional studies with the highly prescribed antihypertensive amlodipine showed that inhibition of bTREK-1 by this agent was voltage-independent and specific. At concentrations that produced near complete block of bTREK-1, amlodipine inhibited voltage-gated K_v1.4 K⁺ and T-type Ca²⁺ currents in AZF cells by less than 10%. At the single-channel level, amlodipine reduced bTREK-1 open probability without altering the unitary conductance. The results demonstrate that selected DHP L-type Ca²⁺ channel antagonists potently inhibit native bTREK-1 K⁺ channels, whereas other Ca²⁺ channel antagonists also inhibit bTREK-1 at higher concentrations. Collectively, organic Ca²⁺ channel antagonists make up the most potent class of TREK-1 inhibitors yet described. Because TREK-1 K⁺ channels are widely expressed in the central nervous and cardiovascular systems, it is possible that some of the therapeutic or toxic effects of frequently prescribed drugs such as amlodipine may be due to their interaction with TREK-1 K⁺ rather L-type Ca²⁺ channels.

Address correspondence to: Dr. John J. Enyeart, Department of Neuroscience, 5196 Graves Hall, College of Medicine and Public Health, The Ohio State University, 333 W. 10th Ave., Columbus, OH 43210-1239. E-mail: enyeart.1{at}osu.edu