Aberrant Splicing Promotes Proteasomal Degradation of L-type Ca(V)1.2 Calcium Channels by Competitive Binding for Ca(V)β Subunits in Cardiac Hypertrophy.
Aberrant Splicing Promotes Proteasomal Degradation of L-type Ca(V)1.2 Calcium Channels by Competitive Binding for Ca(V)β Subunits in Cardiac Hypertrophy.
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DOI：
10.1038/srep35247
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发表时间：
2016-10-12
影响因子：
4.6
通讯作者：
Soong TW
中科院分区：
文献类型：
--
作者：
Hu Z;Wang JW;Yu D;Soon JL;de Kleijn DP;Foo R;Liao P;Colecraft HM;Soong TW
据报道，在压力超负荷引起的心肌肥厚和心力衰竭中，CaV1.2钙通道的表达和活性降低。然而，潜在的机制仍不清楚。在啮齿动物中，我们发现了CaV1.2通道的一个剪接变体，命名为CaV1.2e21+22，它包含一对相互排斥的外显子21和22。这个变异体在新生儿心脏中高度表达。在引起成年小鼠心脏肥厚的横主动脉结扎后14天内，该变体的丰度逐渐增加12.5倍，在扩张型心肌病患者的左心室中也升高。尽管该突变体不传导钙离子，但它减少了野生型CaV1.2通道在细胞表面的表达，从而减少了通过CaV1.2通道的全细胞钙内流。此外，CaV1.2e21+22变异株与CaVβ亚基的相互作用显著高于野生型CaV1.2通道，CaV1.2e21+22与CaVβ亚基的竞争增强了野生型CaV1.2通道的泛素化和随后的蛋白酶体降解。我们的发现表明，在应激状态下，一个特定的新生儿CaV1.2通道剪接变异体在成人心脏中的复苏可能导致心力衰竭。
Decreased expression and activity of CaV1.2 calcium channels has been reported in pressure overload-induced cardiac hypertrophy and heart failure. However, the underlying mechanisms remain unknown. Here we identified in rodents a splice variant of CaV1.2 channel, named CaV1.2e21+22, that contained the pair of mutually exclusive exons 21 and 22. This variant was highly expressed in neonatal hearts. The abundance of this variant was gradually increased by 12.5-folds within 14 days of transverse aortic banding that induced cardiac hypertrophy in adult mouse hearts and was also elevated in left ventricles from patients with dilated cardiomyopathy. Although this variant did not conduct Ca2+ ions, it reduced the cell-surface expression of wild-type CaV1.2 channels and consequently decreased the whole-cell Ca2+ influx via the CaV1.2 channels. In addition, the CaV1.2e21+22 variant interacted with CaVβ subunits significantly more than wild-type CaV1.2 channels, and competition of CaVβ subunits by CaV1.2e21+22 consequently enhanced ubiquitination and subsequent proteasomal degradation of the wild-type CaV1.2 channels. Our findings show that the resurgence of a specific neonatal splice variant of CaV1.2 channels in adult heart under stress may contribute to heart failure.
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影响因子：
5
作者：
MING, Z;NORDIN, C;ARONSON, RS
通讯作者：
ARONSON, RS
影响因子：
25
作者：
Altier, Christophe;Garcia-Caballero, Agustin;Zamponi, Gerald W.
通讯作者：
Zamponi, Gerald W.
影响因子：
37.8
作者：
Antzelevitch, Charles;Pollevick, Guido D.;Wolpert, Christian
通讯作者：
Wolpert, Christian
DOI：
10.1006/bbrc.1995.2705
发表时间：
1995-11-22
影响因子：
3.1
作者：
GIDHJAIN, M;HUANG, BY;ELSHERIF, N
通讯作者：
ELSHERIF, N
影响因子：
4.5
作者：
Liao, Ping;Li, Guang;Soong, Tuck Wah
通讯作者：
Soong, Tuck Wah