Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type Ca2+ channels.
Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type Ca2+ channels.
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DOI：
10.1074/jbc.m111.269951
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发表时间：
2011-12-09
期刊：
影响因子：
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通讯作者：
Koschak A
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文献类型：
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作者：
Bock G;Gebhart M;Scharinger A;Jangsangthong W;Busquet P;Poggiani C;Sartori S;Mangoni ME;Sinnegger-Brauns MJ;Herzig S;Striessnig J;Koschak A
远端（DCRD）和近端调控蛋白之间的分子内相互作用 长Cav1.3 L型C末端内的PCRD结构域 Ca2+通道（Cav1.3L）是一个主要的 它们的电压和Ca2+依赖性门控的决定因素 动力学通过选择性剪接去除这些调控结构域， Cav1.342A通道在更负的条件下激活 电压范围，并表现出更明显的Ca2+依赖性 失活在这里，我们描述了一个新的短剪接变异的发现， （Cav1.343S），其在细胞中以高水平表达。 大脑，但不是心脏。它没有DCRD，但与之相反， Cav1.342A，仍含有PCRD。表达时 与tsA-201细胞中的α 2 δ 1和β 3亚基一起， Cav1.343S也在更负的电压下激活 与Cav1.342A相似，但依赖于Ca2 + 失活不太明显。单通道记录显示， 两种短剪接变体的通道开放概率与 Cav1.3L.近端C末端的存在， Cav1.343S通道通过以下方式保持其调制： 含有Cav1.3和Cav1.2衍生的远端C末端 C-末端肽。通过替代方法去除C-末端调节 剪接也诱导了Ca2+内流的更快衰减， 模拟神经元动作电位序列的电活动。我们 研究结果扩展了功能多样的Cav1.3 L型的范围， 由组织特异性选择性剪接产生的通道。这种多样性可能 有助于微调Ca2+通道信号， 缺乏功能性C末端调节的短变体，防止过度的 神经元爆发性放电过程中Ca~（2+）的积累。这可能 在受影响的神经元中尤为重要 Ca2+诱导的神经变性过程。
An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Cav1.3 L-type Ca2+ channels (Cav1.3L) is a major determinant of their voltage- and Ca2+-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Cav1.342A channels that activate at a more negative voltage range and exhibit more pronounced Ca2+-dependent inactivation. Here we describe the discovery of a novel short splice variant (Cav1.343S) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Cav1.342A, still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Cav1.343S also activated at more negative voltages like Cav1.342A but Ca2+-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Cav1.3L. The presence of the proximal C terminus in Cav1.343S channels preserved their modulation by distal C terminus-containing Cav1.3- and Cav1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca2+ influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Cav1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca2+ channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca2+ accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca2+-induced neurodegenerative processes.