Splicing of an automodulatory domain in Cav1.4 Ca2+ channels confers distinct regulation by calmodulin.
Splicing of an automodulatory domain in Cav1.4 Ca2+ channels confers distinct regulation by calmodulin.
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Cav1.4 Ca2 通道中自调节结构域的剪接赋予钙调蛋白独特的调节作用。
DOI：
10.1085/jgp.201812140
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Lee,Amy
中科院分区：
文献类型：
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作者：
Williams,Brittany;Haeseleer,Françoise;Lee,Amy
Ca2+通过Cav1.4 l型Ca2+通道内流支持黑暗中光感受器突触末端谷氨酸的持续释放，这一过程对视力至关重要。与这一作用一致，Cav1.4表现出弱Ca2+依赖性失活(CDI) -一种由Ca2+结合钙调蛋白（CaM）介导的负反馈调节。CaM与cav通道近端c端域的保守IQ域结合，但在Cav1.4中，c端调制域（CTM）破坏了与CaM的相互作用。外显子47编码CTM的一部分，并在Cav1.4剪接变体（Cav1.4Δex47）中被删除，该变体在人类视网膜中高度表达。Cav1.4Δex47表现出CDI和增强的电压依赖性激活，类似于与先天性静止性2型夜盲症相关的突变引起的，其中CTM被删除（K1591X）。在自然发生的Cav1.4变异中，CDI的存在和非常负的激活阈值令人困惑，因为这些特性预计会对视觉信号不适应，并导致K1591X的夜盲症。在这里，我们发现Cav1.4Δex47和K1591X在CaM的调控中表现出根本的差异。在Cav1.4Δex47中，CDI需要CaM的N端（N叶）和C端（C叶）叶结合Ca2+，而在K1591X中，CDI主要由Ca2+结合到C叶驱动。此外，CaM N叶引起Ca2+依赖性的Cav1.4Δex47激活增强，而不是K1591X。我们得出结论，Cav1.4Δex47中残留的CTM使K1591X中不存在的CaM N瓣调节激活和CDI的一种形式成为可能。与CaM的N叶的相互作用，它比C叶对细胞质Ca2+的整体升高更敏感，可能允许Cav1.4Δex47被比K1591X更大范围的突触Ca2+浓度调节；这可以区分Cav1.4Δex47的正常生理功能和K1591X的病理后果。
Ca2+influx through Cav1.4 L-type Ca2+channels supports the sustained release of glutamate from photoreceptor synaptic terminals in darkness, a process that is critical for vision. Consistent with this role, Cav1.4 exhibits weak Ca2+-dependent inactivation (CDI)—a negative feedback regulation mediated by Ca2+-bound calmodulin (CaM). CaM binds to a conserved IQ domain in the proximal C-terminal domain of Cavchannels, but in Cav1.4, a C-terminal modulatory domain (CTM) disrupts interactions with CaM. Exon 47 encodes a portion of the CTM and is deleted in a Cav1.4 splice variant (Cav1.4Δex47) that is highly expressed in the human retina. Cav1.4Δex47 exhibits CDI and enhanced voltage-dependent activation, similar to that caused by a mutation that is associated with congenital stationary night blindness type 2, in which the CTM is deleted (K1591X). The presence of CDI and very negative activation thresholds in a naturally occurring variant of Cav1.4 are perplexing considering that these properties are expected to be maladaptive for visual signaling and result in night blindness in the case of K1591X. Here we show that Cav1.4Δex47 and K1591X exhibit fundamental differences in their regulation by CaM. In Cav1.4Δex47, CDI requires both the N-terminal (N lobe) and C-terminal (C lobe) lobes of CaM to bind Ca2+, whereas CDI in K1591X is driven mainly by Ca2+binding to the C lobe. Moreover, the CaM N lobe causes a Ca2+-dependent enhancement of activation of Cav1.4Δex47 but not K1591X. We conclude that the residual CTM in Cav1.4Δex47 enables a form of CaM N lobe regulation of activation and CDI that is absent in K1591X. Interaction with the N lobe of CaM, which is more sensitive to global elevations in cytosolic Ca2+than the C lobe, may allow Cav1.4Δex47 to be modulated by a wider range of synaptic Ca2+concentrations than K1591X; this may distinguish the normal physiological function of Cav1.4Δex47 from the pathological consequences of K1591X.