isradipine钙通道阻断的分子机制。药物引起的灭活频道构象的角色。

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Berjukow年代,Marksteiner R,新闻出版总署F, Sinnegger MJ,郝林年代

isradipine钙通道阻断的分子机制。药物引起的灭活频道构象的角色。

J生物化学杂志。2000年7月21日,275 (29):22114 - 20。

PubMed ID

10766758 (在PubMed

]

文摘

灭活的作用渠道构象分子机制的Ca(2 +)通道1块,4-dihydropyridine(设计马力)(+)-isradipine l型通道结构分析(α(1 lc);Berjukow, S。、新闻出版总署、F。Aczel所说,S。Sinnegger, m . J。Mitterdorfer, J。Glossmann, H。郝林,s(1999)生物。274年化学,6154 - 6160)和DHP-sensitive类Ca(2 +)通道突变(α(1 a-dhp);Sinnegger, m . J。王,Z。Grabner, M。郝林,S。Striessnig, J。Glossmann, H。Mitterdorfer, j .(1997)生物。 Chem. 272, 27686-27693) carrying the high affinity determinants of the DHP receptor site but inactivating at different rates. Ca(2+) channel inactivation was modulated by coexpressing the alpha(1A-DHP)- or alpha(1Lc)-subunits in Xenopus oocytes with either the beta(2a)- or the beta(1a)-subunit and amino acid substitutions in L-type segment IVS6 (I1497A, I1498A, and V1504A). Contrary to a modulated receptor mechanism assuming high affinity DHP binding to the inactivated state we observed no clear correlation between steady state inactivation and Ca(2+) channel block by (+)-isradipine: (i) a 3-fold larger fraction of alpha(1A-DHP)/beta(1a) channels in steady state inactivation at -80 mV (compared with alpha(1A-DHP)/beta(2a)) did not enhance the block by (+)-isradipine; (ii) different steady state inactivation of alpha(1Lc) mutants at -30 mV did not correlate with voltage-dependent channel block; and (iii) the midpoint-voltages of the inactivation curves of slowly inactivating L-type constructs and more rapidly inactivating alpha(1Lc)/beta(1a) channels were shifted to a comparable extent to more hyperpolarized voltages. A kinetic analysis of (+)-isradipine interaction with different L-type channel constructs revealed a drug-induced inactivated state. Entry and recovery from drug-induced inactivation are modulated by intrinsic inactivation determinants, suggesting a synergism between intrinsic inactivation and DHP block.

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药物靶点

药物	目标	类	生物	药理作用	行动
Isradipine	压敏电阻器l型钙通道亚基alpha-1C	蛋白质	人类	是的	抑制剂	细节