美国哥伦比亚大学Steven O. Marx、哈佛医学院Marian Kalocsay等研究人员合作利用邻近蛋白质组学揭示肾上腺素CaV1.2通道的激活机制。这一研究成果2020年1月22日在线发表在国际学术期刊《自然》上。
Title: Mechanism of adrenergic Ca V 1.2 stimulation revealed by proximity proteomics
Author: Guoxia Liu, Arianne Papa, Alexander N. Katchman, Sergey I. Zakharov, Daniel Roybal, Jessica A. Hennessey, Jared Kushner, Lin Yang, Bi-Xing Chen, Alexander Kushnir, Katerina Dangas, Steven P. Gygi, Geoffrey S. Pitt, Henry M. Colecraft, Manu Ben-Johny, Marian Kalocsay, Steven O. Marx
Issue&Volume: 2020-01-22
Abstract: Increased cardiac contractility during the fight-or-flight response is caused by β-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1,2,3,4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 α1C and β subunits that can no longer be phosphorylated by protein kinase A—an essential downstream mediator of β-adrenergic signalling—suggesting that non-channel factors are also required. Here we identify the mechanism by which β-adrenergic agonists stimulate voltage-gated calcium channels. We express α1C or β2B subunits conjugated to ascorbate peroxidase5 in mouse hearts, and use multiplexed quantitative proteomics6,7 to track hundreds of proteins in the proximity of CaV1.2. We observe that the calcium-channel inhibitor Rad8,9, a monomeric G protein, is enriched in the CaV1.2 microenvironment but is depleted during β-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for β subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of CaV1.3 and CaV2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.
DOI: 10.1038/s41586-020-1947-z
Source: https://www.nature.com/articles/s41586-020-1947-z
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html
本期文章:《自然》:Online/在线发表