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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: |
Katz, M.  ORCID: https://orcid.org/0000-0002-0327-3026, Subramaniam, S. ORCID: https://orcid.org/0000-0001-9574-2100, Chomsky-Hecht, O., Tsemakhovich, V. ORCID: https://orcid.org/0000-0002-4969-6497, Flockerzi, V., Klussmann, E. ORCID: https://orcid.org/0000-0003-4004-5003, Hirsch, J.A. ORCID: https://orcid.org/0000-0001-7544-8668, Weiss, S. ORCID: https://orcid.org/0000-0002-0981-6917 and Dascal, N. ORCID: https://orcid.org/0000-0002-5397-4146
|
| 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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