Cited by 243Ion channel regulation and functionCardiac electrophysiology and arrhythmiasReceptor Mechanisms and Signaling

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Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics

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Liu, Guoxia, Papa, Arianne, Katchman, Alexander N., Zakharov, Sergey I., Roybal, Daniel, Hennessey, Jessica A., Kushner, Jared, Yang, Lin, Chen, Bi-Xing, Kushnir, Alexander, Dangas, Katerina, Gygi, Steven P., Pitt, Geoffrey S., Colecraft, Henry M., Ben-Johny, Manu, Kalocsay, Marian, Marx, Steven O.·2020·Nature

DOI 10.1038/s41586-020-1947-zPMC PMC7018383

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Abstract

Increased cardiac contractility during the fight-or-flight response is caused by β-adrenergic augmentation of Ca V 1.2 voltage-gated calcium channels 1-4. However, this augmentation persists in transgenic murine hearts expressing mutant Ca V 1.2 α 1C 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 α 1C or β 2B subunits conjugated to ascorbate peroxidase 5 in mouse hearts, and use multiplexed quantitative proteomics 6,7 to track hundreds of proteins in the proximity of Ca V 1.2. We observe that the calcium-channel inhibitor Rad 8,9, a monomeric G protein, is enriched in the Ca V 1.2 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 Ca V 1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of Ca V 1.3 and Ca V 2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.

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Authors: Liu, G., Papa, A., Katchman, A. N., Zakharov, S. I., Roybal, D., Hennessey, J. A., Kushner, J., Yang, L., Chen, B.-X., Kushnir, A., Dangas, K., Gygi, S. P., Pitt, G. S., Colecraft, H. M., Ben-Johny, M., Kalocsay, M., & Marx, S. O.
Affiliations: Columbia University (US)
Harvard University (US)
Weill Cornell Medicine (US)
Columbia University Irving Medical Center (US)
Corresponding author: Kalocsay, Marian
Marx, Steven O.
ORCID: Liu, Guoxia
Papa, Arianne
Katchman, Alexander N.
Zakharov, Sergey I.
Roybal, Daniel
Hennessey, Jessica A.
Kushner, Jared
Yang, Lin
Kushnir, Alexander
Gygi, Steven P.
Pitt, Geoffrey S.
Colecraft, Henry M.
Kalocsay, Marian
Marx, Steven O.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2020-01-22
Volume: 577
Issue: 7792
Pages: 695-700
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-020-1947-z
PMC: PMC7018383
OpenAlex: W3003002159
Cited by: 243
References: 74
Citations by year: 2026: 23 · 2025: 31 · 2024: 36 · 2023: 36 · 2022: 39 · 2021: 50 · 2020: 28
FWCI: 12.41
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (UL1TR001873)
National Heart, Lung, and Blood Institute (R01HL113136, F31HL142178, T32HL120826, R01HL126735, R01HL121253, R01HL140934, R01HL146149, T32HL160520, T32HL007343, T32HL007854)
National Cancer Institute (P30CA013696)
National Center for Advancing Translational Sciences
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: Cav1.2, voltage-gated calcium channels, beta-adrenergic signaling, protein kinase A, REM, G proteins, channel phosphorylation, channel inhibition, cardiac contractility, proximity proteomics, ascorbate peroxidase, Cav1.3, CaV2.2, calcium current
MeSH terms: Protein Domains, Cyclic AMP, Animals, Female, Humans, Male, Myocardium, Phosphorylation, Receptors, Adrenergic, beta, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, ras Proteins, Monomeric GTP-Binding Proteins, Calcium Channels, L-Type, Calcium Channels, N-Type, Heterotrimeric GTP-Binding Proteins, Protein Subunits, Proteomics, Mice, HEK293 Cells, Cellular Microenvironment

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Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics

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