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Am J Physiol Cell Physiol 278: C570-C581, 2000;
0363-6143/00 $5.00
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Vol. 278, Issue 3, C570-C581, March 2000

Pharmacological activation of cloned intermediate- and small-conductance Ca2+-activated K+ channels

Colin A. Syme, Aaron C. Gerlach, Ashvani K. Singh, and Daniel C. Devor

Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

We previously characterized 1-ethyl-2-benzimidazolinone (1-EBIO), as well as the clinically useful benzoxazoles, chlorzoxazone (CZ), and zoxazolamine (ZOX), as pharmacological activators of the intermediate-conductance Ca2+-activated K+ channel, hIK1. The mechanism of activation of hIK1, as well as the highly homologous small-conductance, Ca2+-dependent K+ channel, rSK2, was determined following heterologous expression in Xenopus oocytes using two-electrode voltage clamp (TEVC) and excised, inside-out patch-clamp techniques. 1-EBIO, CZ, and ZOX activated both hIK1 and rSK2 in TEVC and excised inside-out patch-clamp experiments. In excised, inside-out patches, 1-EBIO and CZ induced a concentration-dependent activation of hIK1, with half-maximal (K1/2) values of 84 µM and 98 µM, respectively. Similarly, CZ activated rSK2 with a K1/2 of 87 µM. In the absence of CZ, the Ca2+-dependent activation of hIK1 was best fit with a K1/2 of 700 nM and a Hill coefficient (n) of 2.0. rSK2 was activated by Ca2+ with a K1/2 of 700 nM and an n of 2.5. Addition of CZ had no effect on either the K1/2 or n for Ca2+-dependent activation of either hIK1 or rSK2. Rather, CZ increased channel activity at all Ca2+ concentrations (Vmax). Event-duration analysis revealed hIK1 was minimally described by two open and three closed times. Activation by 1-EBIO had no effect on tau o1, tau o2, or tau c1, whereas tau c2 and tau c3 were reduced from 9.0 and 92.6 ms to 5.0 and 44.1 ms, respectively. In conclusion, we define 1-EBIO, CZ, and ZOX as the first known activators of hIK1 and rSK2. Openers of IK and SK channels may be therapeutically beneficial in cystic fibrosis and vascular diseases.

hIK1 channel; rSK2 channel; chlorzoxazone; zoxazolamine; 1-ethyl-2-benzimidazolinone


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