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Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics

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  • Guoxia Liu

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Arianne Papa

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Alexander N. Katchman

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Sergey I. Zakharov

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Daniel Roybal

    (Vagelos College of Physicians and Surgeons)

  • Jessica A. Hennessey

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Jared Kushner

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Lin Yang

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Bi-Xing Chen

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Alexander Kushnir

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Katerina Dangas

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Steven P. Gygi

    (Harvard Medical School)

  • Geoffrey S. Pitt

    (Weill Cornell Medical College)

  • Henry M. Colecraft

    (Columbia University, Vagelos College of Physicians and Surgeons
    Vagelos College of Physicians and Surgeons)

  • Manu Ben-Johny

    (Columbia University, Vagelos College of Physicians and Surgeons)

  • Marian Kalocsay

    (Harvard Medical School)

  • Steven O. Marx

    (Columbia University, Vagelos College of Physicians and Surgeons
    Vagelos College of Physicians and Surgeons)

Abstract

Increased cardiac contractility during the fight-or-flight response is caused by β-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1–4. 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.

Suggested Citation

  • 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, 2020. "Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics," Nature, Nature, vol. 577(7792), pages 695-700, January.
  • Handle: RePEc:nat:nature:v:577:y:2020:i:7792:d:10.1038_s41586-020-1947-z
    DOI: 10.1038/s41586-020-1947-z
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    Cited by:

    1. Dingxi Zhou & Mariana Borsa & Daniel J. Puleston & Susanne Zellner & Jesusa Capera & Sharon Sanderson & Martina Schifferer & Svenja S. Hester & Xin Ge & Roman Fischer & Luke Jostins & Christian Behren, 2022. "Mapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Travis J. Morgenstern & Neha Nirwan & Erick O. Hernández-Ochoa & Hugo Bibollet & Papiya Choudhury & Yianni D. Laloudakis & Manu Johny & Roger A. Bannister & Martin F. Schneider & Daniel L. Minor & Hen, 2022. "Selective posttranslational inhibition of CaVβ1-associated voltage-dependent calcium channels with a functionalized nanobody," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Maartje Westhoff & Silvia G. Villar & Taylor L. Voelker & Phung N. Thai & Heather C. Spooner & Alexandre D. Costa & Padmini Sirish & Nipavan Chiamvimonvat & Eamonn J. Dickson & Rose E. Dixon, 2024. "BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Declan Manning & L. Fernando Santana, 2022. "Regulating voltage-gated ion channels with nanobodies," Nature Communications, Nature, vol. 13(1), pages 1-2, December.

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