Department of Chemistry, University of California, Davis, CA 95616, USA.
Biomolecules. 2021 Dec 2;11(12):1811. doi: 10.3390/biom11121811.
L-type voltage-gated Ca channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca sensor proteins, calmodulin (CaM) and Ca binding Protein 1 (CaBP1), that oppositely control Ca-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif within the C-terminal cytosolic domain of CaV, which promotes increased channel open probability under basal conditions. At elevated cytosolic Ca levels (caused by CaV channel opening), Ca-bound CaM binding to CaV is essential for promoting rapid Ca-dependent channel inactivation (CDI). By contrast, CaV binding to CaBP1 prevents CDI and promotes Ca-induced channel opening (called CDF). In this review, I provide an overview of the known structures of CaM and CaBP1 and their structural interactions with the IQ-motif to help understand how CaM promotes CDI, whereas CaBP1 prevents CDI and instead promotes CDF. Previous electrophysiology studies suggest that Ca-free forms of CaM and CaBP1 may pre-associate with CaV under basal conditions. However, previous Ca binding data suggest that CaM and CaBP1 are both calculated to bind to Ca with an apparent dissociation constant of ~100 nM when CaM or CaBP1 is bound to the IQ-motif. Since the neuronal basal cytosolic Ca concentration is ~100 nM, nearly half of the neuronal CaV channels are suggested to be bound to Ca-bound forms of either CaM or CaBP1 under basal conditions. The pre-association of CaV with calcified forms of CaM or CaBP1 are predicted here to have functional implications. The Ca-bound form of CaBP1 is proposed to bind to CaV under basal conditions to block CaV binding to CaM, which could explain how CaBP1 might prevent CDI.
L 型电压门控钙通道（CaV1.2 和 CaV1.3，称为 CaV）与钙传感器蛋白钙调蛋白（CaM）和钙结合蛋白 1（CaBP1）相互作用，这两种蛋白反向控制钙依赖性通道活性。CaM 和 CaBP1 都可以与 CaV 胞质 C 端末端的 IQ 基序结合，在基础条件下促进通道开放概率增加。在细胞内 Ca 水平升高（由 CaV 通道开放引起）的情况下，与 CaV 结合的 Ca 结合的 CaM 结合对于促进快速的钙依赖性通道失活（CDI）是必需的。相比之下，CaV 与 CaBP1 结合可防止 CDI，并促进钙诱导的通道开放（称为 CDF）。在这篇综述中，我提供了 CaM 和 CaBP1 的已知结构概述及其与 IQ 基序的结构相互作用，以帮助理解 CaM 如何促进 CDI，而 CaBP1 防止 CDI，而是促进 CDF。以前的电生理学研究表明，在基础条件下，无 Ca 形式的 CaM 和 CaBP1 可能与 CaV 预先结合。然而，以前的 Ca 结合数据表明，当 CaM 或 CaBP1 与 IQ 基序结合时，CaM 和 CaBP1 都被计算为以约 100 nM 的表观解离常数结合 Ca。由于神经元的基础细胞浆 Ca 浓度约为 100 nM，因此在基础条件下，近一半的神经元 CaV 通道被认为与 Ca 结合形式的 CaM 或 CaBP1 结合。这里预测，CaV 与 CaM 或 CaBP1 的钙化形式的预先结合具有功能意义。CaBP1 的 Ca 结合形式被提议在基础条件下与 CaV 结合，以阻止 CaV 与 CaM 结合，这可以解释 CaBP1 如何防止 CDI。
