Pharmacological activation of cloned intermediate- and small-conductance Ca(2+)-activated K(+) channels |
| |
Authors: | Syme C A Gerlach A C Singh A K Devor D C |
| |
Institution: | Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. |
| |
Abstract: | We previouslycharacterized 1-ethyl-2-benzimidazolinone (1-EBIO), as well as theclinically useful benzoxazoles, chlorzoxazone (CZ), and zoxazolamine(ZOX), as pharmacological activators of the intermediate-conductanceCa2+-activated K+ channel, hIK1. The mechanismof activation of hIK1, as well as the highly homologoussmall-conductance, Ca2+-dependent K+ channel,rSK2, was determined following heterologous expression inXenopus 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 aconcentration-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 activationof hIK1 was best fit with a K1/2 of 700 nM and aHill coefficient (n) of 2.0. rSK2 was activated byCa2+ with a K1/2 of 700 nM and ann of 2.5. Addition of CZ had no effect on either theK1/2 or n for Ca2+-dependentactivation of either hIK1 or rSK2. Rather, CZ increased channelactivity at all Ca2+ concentrations(Vmax). Event-duration analysis revealed hIK1 wasminimally described by two open and three closed times. Activation by1-EBIO had no effect on o1, o2, orc1, whereas c2 and c3 werereduced from 9.0 and 92.6 ms to 5.0 and 44.1 ms, respectively. Inconclusion, we define 1-EBIO, CZ, and ZOX as the first known activatorsof hIK1 and rSK2. Openers of IK and SK channels may be therapeuticallybeneficial in cystic fibrosis and vascular diseases. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
| 点击此处可从《American journal of physiology》浏览原始摘要信息 |
| 点击此处可从《American journal of physiology》下载免费的PDF全文 |
|