Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices
Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices
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DOI：
10.1073/pnas.0511322103
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发表时间：
2006-03-07
影响因子：
11.1
通讯作者：
Armstrong, DL
中科院分区：
文献类型：
--
作者：
Erxleben, C;Liao, YH;Armstrong, DL
质膜中的钙通道很少在任何时间保持开放超过一毫秒，这避免了细胞内钙升高到有毒水平。然而，CaV1 家族的二氢吡啶敏感钙通道选择性地将电激发与内分泌分泌、心血管收缩性和神经元转录耦合，具有独特的第二种门控模式，即“模式 2”，涉及更长持续时间的频繁开放。在这里，我们报告了两种人类疾病，环孢菌素神经毒性和蒂莫西综合征，增加了重组兔 CaV1.2 通道的模式 2 门控。在每种情况下，模式 2 门控取决于结构域 I（Ser-439，蒂莫西综合征）或结构域 IV（Ser-1517，环孢菌素）中 S6 螺旋胞质末端的 Ser 残基。两个 Ser 均位于 II 型钙调蛋白依赖性蛋白激酶的共有序列中。通过药理学抑制 II 型钙调蛋白依赖性蛋白激酶或将 Ser 残基突变为 Ala 可防止模式 2 门控的增加。我们认为CaV1.2通道蛋白的异常磷酸化或“磷酸化病”导致与蒂莫西综合征和移植患者的慢性环孢菌素治疗相关的兴奋性毒性。
Calcium channels in the plasma membrane rarely remain open for much more than a millisecond at any one time, which avoids raising intracellular calcium to toxic levels. However, the dihydropyridine-sensitive calcium channels of the CaV1 family, which selectively couple electrical excitation to endocrine secretion, cardiovascular contractility, and neuronal transcription, have a unique second mode of gating, "mode 2," that involves frequent openings of much longer duration. Here we report that two human conditions, cyclosporin neurotoxicity and Timothy syndrome, increase mode 2 gating of the recombinant rabbit CaV1.2 channel. In each case mode 2 gating depends on a Ser residue at the cytoplasmic end of the S6 helix in domain I (Ser-439, Timothy syndrome) or domain IV (Ser-1517, cyclosporin). Both Ser reside in consensus sequences for type II calmodulin-dependent protein kinase. Pharmacologically inhibiting type II calmodulin-dependent protein kinase or mutating the Ser residues to Ala prevents the increase in mode 2 gating. We propose that aberrant phosphorylation, or "phosphorylopathy," of the CaV1.2 channel protein contributes to the excitotoxicity associated with Timothy syndrome and with chronic cyclosporin treatment of transplant patients.