Penitrem A as a Tool for Understanding the Role of Large Conductance Ca2+/Voltage-Sensitive K+ Channels in Vascular Function

Penitrem A as a Tool for Understanding the Role of Large Conductance Ca2+/Voltage-Sensitive K+ Channels in Vascular Function

Asano S; Bratz I N; Berwick Z C; Fancher I S; Tune J D; Dick G M

Journal of Pharmacology and Experimental Therapeutics

2012

2012-08

Large conductance, Ca2+/voltage-sensitive K+ channels (BK channels) are well characterized, but their physiological roles, often determined through pharmacological manipulation, are less clear. Iberiotoxin is considered the "gold standard" antagonist, but cost and membrane-impermeability limit its usefulness. Economical and membrane-permeable alternatives could facilitate the study of BK channels. Thus, we characterized the effect of penitrem A, a tremorigenic mycotoxin, on BK channels and demonstrate its utility for studying vascular function in vitro and in vivo. Whole-cell currents from human embryonic kidney 293 cells transfected with hSlo alpha or alpha + beta 1 were blocked >95% by penitrem A (IC50 6.4 versus 64.4 nM; p < 0.05). Furthermore, penitrem A inhibited BK channels in inside-out and cell-attached patches, whereas iberiotoxin could not. Inhibitory effects of penitrem A on whole-cell K+ currents were equivalent to iberiotoxin in canine coronary smooth muscle cells. As for specificity, penitrem A had no effect on native delayed rectifier K+ currents, cloned voltage-dependent Kv1.5 channels, or native ATP-dependent K-ATP current. Penitrem A enhanced the sensitivity to K+-induced contraction in canine coronary arteries by 23 +/- 5% (p < 0.05) and increased the blood pressure response to phenylephrine in anesthetized mice by 36 +/- 11% ( p < 0.05). Our data indicate that penitrem A is a useful tool for studying the role of BK channels in vascular function and is practical for cell and tissue (in vitro)

metabolic syndrome; Pharmacology & Pharmacy; expression; calcium; smooth-muscle; coronary vasodilation; ca2+; activated potassium channel; beta-1 subunit; bkca channels; elevated blood-pressure; sparks

Journal Article or Conference Abstract Publication

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