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Inhibition of the type 1 inositol 1,4,5-trisphosphate-sensitive Ca2+ channel by calmodulin antagonists

机译：钙调蛋白拮抗剂对1型肌醇1,4,5-三磷酸敏感性Ca2 +通道的抑制作用

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This study describes the effects of a number of calmodulin antagonists on the cerebellar type 1 inositol 1,4,5-trisphosphate (InsP(3)) receptor. All the antagonists tested (trifluoperazine, fluphenazine, chlorpromazine and calmidazolium) inhibited the extent of InsP(3)-induced Ca2+ release (IICR) with similar IC50 values between 60 and 85 muM). They did not affect the efficacy of InsP(3) to release Ca2+, since the concentrations of InsP(3) required to cause half-maximal release was little affected in the presence of these agents. Tn addition, these agents did not affect InsP(3) binding to its receptor. Stopped-flow studies to determine the rate constants of IICR showed this process to be biphasic with a fast and slow component. All the calmodulin antagonists appeared to reduce the rate constants for Ca2+ release in a phase-specific manner, preferentially reducing the fast phase component. Chlorpromazine (75 muM) appeared to have the most potent effect on the fast phase rate constant, reducing it from 1.0 to 0.08 s(-1), while only reducing the rate constant for the slow phase about two fold (0.2-0.08 s(-1)). The fact that calmodulin itself inhibits both IICR and InsP(3) binding, while these calmodulin antagonists also reduce Ca2+ release and do not affect InsP(3) binding, suggests that the mechanism of action of these agents is unlikely to be due to the reversal of the modulatory action of calmodulin on this receptor. (C) 2001 Elsevier Science Inc. All rights reserved. [References: 29]
机译：这项研究描述了许多钙调蛋白拮抗剂对小脑1型肌醇1,4,5-三磷酸（InsP（3））受体的影响。测试的所有拮抗剂（三氟拉嗪，氟奋乃静，氯丙嗪和卡地咪唑）均抑制InsP（3）诱导的Ca2 +释放（IICR）的程度，IC50值在60至85μM之间。它们不影响InsP（3）释放Ca2 +的功效，因为引起这些药物半数最大释放所需的InsP（3）浓度几乎不受这些试剂的影响。此外，这些药物不会影响InsP（3）与其受体的结合。停止流动研究以确定IICR的速率常数，表明该过程是双相的，具有快速和慢速成分。所有钙调蛋白拮抗剂似乎都以特定于相的方式降低了Ca2 +释放的速率常数，优先降低了快速相成分。氯丙嗪（75μM）似乎对快相速率常数具有最强的作用，将其从1.0降低至0.08 s（-1），而仅将慢相速率常数降低约两倍（0.2-0.08 s（ -1））。钙调蛋白本身可以抑制IICR和InsP（3）结合，而这些钙调蛋白拮抗剂也可以减少Ca2 +释放并且不影响InsP（3）结合，这一事实表明，这些药物的作用机制不太可能是由于逆转钙调蛋白对该受体的调节作用（C）2001 Elsevier Science Inc.保留所有权利。 [参考：29]

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