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DOI10.1073/pnas.2100021118
Reconstitution of β-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms
Katz M.; Subramaniam S.; Chomsky-Hecht O.; Tsemakhovich V.; Flockerzi V.; Klussmann E.; Hirsch J.A.; Weiss S.; Dascal N.
发表日期2021
ISSN0027-8424
卷号118期号:21
英文摘要L-type voltage-gated CaV1.2 channels crucially regulate cardiac muscle contraction. Activation of β-adrenergic receptors (β-AR) augments contraction via protein kinase A (PKA)–induced increase of calcium influx through CaV1.2 channels. To date, the full β-AR cascade has never been heterologously reconstituted. A recent study identified Rad, a CaV1.2 inhibitory protein, as essential for PKA regulation of CaV1.2. We corroborated this finding and reconstituted the complete pathway with agonist activation of β1-AR or β2-AR in Xenopus oocytes. We found, and distinguished between, two distinct pathways of PKA modulation of CaV1.2: Rad dependent (∼80% of total) and Rad independent. The reconstituted system reproduces the known features of β-AR regulation in cardiomyocytes and reveals several aspects: the differential regulation of posttranslationally modified CaV1.2 variants and the distinct features of β1-AR versus β2-AR activity. This system allows for the addressing of central unresolved issues in the β-AR–CaV1.2 cascade and will facilitate the development of therapies for catecholamine-induced cardiac pathologies. © 2021 National Academy of Sciences. All rights reserved.
英文关键词adrenergic; Calcium channel; cardiac; heterologous; protein kinase A
语种英语
scopus关键词beta 1 adrenergic receptor; beta 2 adrenergic receptor; beta adrenergic receptor; binding protein; calcium channel L type; cyclic AMP dependent protein kinase; L type voltage gated CaV1 2 channel; Rad protein; unclassified drug; beta adrenergic receptor; calcium; calcium channel L type; cyclic AMP; cyclic AMP dependent protein kinase; isoprotein; L-type calcium channel alpha(1C); Ras protein; RNA; RRAD protein, human; adult; animal cell; Article; cardiac muscle cell; controlled study; enzyme regulation; female; nonhuman; oocyte; priority journal; protein expression; protein processing; signal transduction; Xenopus; animal; cytology; gene expression regulation; genetics; human; ion transport; Leporidae; metabolism; mouse; mutation; Xenopus laevis; Animals; Calcium; Calcium Channels, L-Type; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Gene Expression Regulation; Humans; Ion Transport; Mice; Mutation; Myocytes, Cardiac; Oocytes; Protein Isoforms; Rabbits; ras Proteins; Receptors, Adrenergic, beta; RNA; Xenopus laevis
来源期刊Proceedings of the National Academy of Sciences of the United States of America (IF:9.58[JCR-2018],10.6[5-Year])
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/251172
作者单位Sackler School of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel; Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, 66421, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel
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Katz M.,Subramaniam S.,Chomsky-Hecht O.,et al. Reconstitution of β-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms[J],2021,118(21).
APA Katz M..,Subramaniam S..,Chomsky-Hecht O..,Tsemakhovich V..,Flockerzi V..,...&Dascal N..(2021).Reconstitution of β-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms.Proceedings of the National Academy of Sciences of the United States of America,118(21).
MLA Katz M.,et al."Reconstitution of β-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms".Proceedings of the National Academy of Sciences of the United States of America 118.21(2021).
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