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Hennessey, Jessica

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Hennessey

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Hennessey, Jessica

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    Mechanism of Adrenergic CaV1.2 Stimulation Revealed by Proximity Proteomics
    (Springer Science and Business Media LLC, 2020-01-22) Liu, Guoxia; Papa, Arianne; Katchman, Alexander N.; Zakharov, Sergey I.; Roybal, Daniel; Hennessey, Jessica; Kushner, Jared; Yang, Lin; Chen, Bi-Xing; Kushnir, Alexander; Dangas, Katerina; Gygi, Steven; Pitt, Geoffrey S.; Colecraft, Henry M.; Ben-Johny, Manu; Kalocsay, Marian; Marx, Steven O.
    Increased cardiac contractility during fight-or-flight response is caused by b-adrenergic augmentation of CaV1.2 channels. In transgenic murine hearts expressing fully PKA phosphorylation-site-deficient mutant CaV1.2 a1C and b subunits, this regulation persists, implying involvement of extra-channel factors. Here, we identify the mechanism by which b-adrenergic agonists stimulate voltage-gated Ca2+ channels. We expressed ascorbate-peroxidase-conjugated-a1C or -b2B subunits in mouse hearts and used multiplexed, quantitative proteomics to track hundreds of proteins in proximity of CaV1.2. We observed that the Ca2+ channel inhibitor Rad, a monomeric G-protein, is enriched in the CaV1.2 micro-environment but is depleted during b-adrenergic stimulation. PKA-catalyzed phosphorylation of specific Ser residues on Rad decreases its affinity for auxiliary b-subunits and relieves constitutive inhibition of CaV1.2 observed as an increase in channel open probability. Expression of Rad or Rem, a homolog, also imparted PKA-induced stimulation of CaV1.3 and CaV2.2, revealing an evolutionarily conserved mechanism that confers adrenergic-modulation upon voltage-gated Ca2+ channels.