RT Journal Article
SR Electronic
T1 Penitrem A as a Tool for Understanding the Role of Large Conductance Ca<sup>2+</sup>/Voltage-Sensitive K<sup>+</sup> Channels in Vascular Function
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 453
OP 460
DO 10.1124/jpet.111.191072
VO 342
IS 2
A1 Asano, Shinichi
A1 Bratz, Ian N.
A1 Berwick, Zachary C.
A1 Fancher, Ibra S.
A1 Tune, Johnathan D.
A1 Dick, Gregory M.
YR 2012
UL http://jpet.aspetjournals.org/content/342/2/453.abstract
AB 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 α or α + β1 were blocked &gt;95% by penitrem A (IC50 6.4 versus 64.4 nM; p &lt; 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 KATP current. Penitrem A enhanced the sensitivity to K+-induced contraction in canine coronary arteries by 23 ± 5% (p &lt; 0.05) and increased the blood pressure response to phenylephrine in anesthetized mice by 36 ± 11% (p &lt; 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) studies as well as anesthetized animal (in vivo) experiments.