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

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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., Subramaniam, S., Chomsky-Hecht, O., Tsemakhovich, V., Flockerzi, V., Klussmann, E., Hirsch, J.A., 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, Mice, Rabbits, 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
Additional Information:	Published under the PNAS license (https://www.pnas.org/author-center/publication-charges).
Official Publication:	https://doi.org/10.1073/pnas.2100021118
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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