Penitrem A as a tool for understanding the role of large conductance Ca2+/ voltage-sensitive K+ channels in vascular function

Shinichi Asano, Ian N. Bratz, Zachary C. Berwick, Ibra S. Fancher, Johnathan D. Tune, Gregory M. Dick

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 >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 KATP 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) studies as well as anesthetized animal (in vivo) experiments.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume342
Issue number2
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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