含亮氨酸丰富重复蛋白 10 对心脏 L 型钙通道的调控。

Channels (Austin, Tex.) Pub Date : 2024-12-01 Epub Date: 2024-05-19 DOI:10.1080/19336950.2024.2355121
Natthaphat Siri-Angkul, Timothy J Kamp
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引用次数: 0

摘要

L 型钙通道(LTCC)是 Ca2+ 进入心肌细胞的主要通道,对兴奋-收缩耦合至关重要,因此在调节整体心脏功能方面发挥着核心作用。LTCC 的功能由多种信号通路和附属蛋白进行微调。富亮氨酸重复序列蛋白 10(LRRC10)是一种研究较少的心肌细胞特异性蛋白,最近被发现是 LTCC 的调节因子。LRRC10 对 LTCC 的功能有显著影响,在异源表达系统中,它通过改变通道的门控而不改变其表面膜的表达,使 L 型 Ca2+ 电流(ICa,L)的振幅增加了一倍多。小鼠和斑马鱼心脏中 LRRC10 表达的基因消减会导致 ICa,L 密度显著降低,并导致小鼠出现缓慢进行性扩张型心肌病。在扩张型心肌病和原因不明的夜间心脏猝死综合征中发现了 LRRC10 的罕见序列变异,但这些变异尚未与疾病明确相关。然而,DCM 相关变体 I195T 将 LRRC10 从 ICa,L 的增效剂转变为 ICa,L 的抑制剂,从而说明了 LRRC10 介导的 ICa,L 调节具有广泛的动态范围。本综述重点介绍 LRRC10 调节 LTCC 的现代知识,并讨论未来研究的潜在方向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cardiac L-type calcium channel regulation by Leucine-Rich Repeat-Containing Protein 10.

L-type calcium channels (LTCCs), the major portal for Ca2+ entry into cardiomyocytes, are essential for excitation-contraction coupling and thus play a central role in regulating overall cardiac function. LTCC function is finely tuned by multiple signaling pathways and accessory proteins. Leucine-rich repeat-containing protein 10 (LRRC10) is a little studied cardiomyocyte-specific protein recently identified as a modulator of LTCCs. LRRC10 exerts a remarkable effect on LTCC function, more than doubling L-type Ca2+ current (ICa,L) amplitude in a heterologous expression system by altering the gating of the channels without changing their surface membrane expression. Genetic ablation of LRRC10 expression in mouse and zebrafish hearts leads to a significant reduction in ICa,L density and a slowly progressive dilated cardiomyopathy in mice. Rare sequence variants of LRRC10 have been identified in dilated cardiomyopathy and sudden unexplained nocturnal cardiac death syndrome, but these variants have not been clearly linked to disease. Nevertheless, the DCM-associated variant, I195T, converted LRRC10 from a ICa,L potentiator to a ICa,L suppressor, thus illustrating the wide dynamic range of LRRC10-mediated ICa,L regulation. This review focuses on the contemporary knowledge of LTCC modulation by LRRC10 and discusses potential directions for future investigations.

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