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Reconstitution of β-adrenergic regulation of Ca(V)1.2: Rad-dependent and Rad-independent protein kinase A mechanisms

Item Type:Article
Title:Reconstitution of β-adrenergic regulation of Ca(V)1.2: Rad-dependent and Rad-independent protein kinase A mechanisms
Creators Name:Katz, M. and Subramaniam, S. and Chomsky-Hecht, O. and Tsemakhovich, V. and Flockerzi, V. and Klussmann, E. and Hirsch, J.A. and Weiss, S. and Dascal, N.
Abstract:L-type voltage-gated Ca(V)1.2 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 Ca(V)1.2 channels. To date, the full β-AR cascade has never been heterologously reconstituted. A recent study identified Rad, a Ca(V)1.2 inhibitory protein, as essential for PKA regulation of Ca(V)1.2. 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 Ca(V)1.2: 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 Ca(V)1.2 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–Ca(V)1.2 cascade and will facilitate the development of therapies for catecholamine-induced cardiac pathologies.
Keywords:Calcium Channel, Adrenergic, Heterologous, Protein Kinase A, Cardiac, Animals, Xenopus laevis
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences
Volume:118
Number:21
Page Range:e2100021118
Date:17 May 2021
Official Publication:https://doi.org/10.1073/pnas.2100021118
PubMed:View item in PubMed
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https://edoc.mdc-berlin.de/19690/Preprint version

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