![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
Tools
Tools
Preview |
PDF (Original Article)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
3MB |
![[thumbnail of Supplementary Information]](https://edoc.mdc-berlin.de/style/images/fileicons/other.png) |
Other (Supplementary Information)
7MB |
| Item Type: | Article |
|---|---|
| Title: | Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca(2+) channel may modulate its β-adrenergic regulation |
| Creators Name: | Oz, S., Keren-Raifman, T., Sharon, T., Subramaniam, S., Pallien, T., Katz, M., Tsemakhovich, V., Sholokh, A., Watad, B., Tripathy, D.R., Sasson, G., Chomsky-Hecht, O., Vysochek, L., Schulz-Christian, M., Fecher-Trost, C., Zühlke, K., Bertinetti, D., Herberg, F.W., Flockerzi, V., Hirsch, J.A., Klussmann, E., Weiss, S. and Dascal, N. |
| Abstract: | BACKGROUND: The β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated CaV1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits. Free PKAC phosphorylates the inhibitory protein Rad, leading to increased Ca2+ influx. In cardiomyocytes, the core subunit of CaV1.2, CaV1.2α1, exists in two forms: full-length or truncated (lacking the distal C-terminus (dCT)). Signaling efficiency is believed to emanate from protein interactions within multimolecular complexes, such as anchoring PKA (via PKAR) to CaV1.2α1 by A-kinase anchoring proteins (AKAPs). However, AKAPs are inessential for βAR regulation of CaV1.2 in heterologous models, and their role in cardiomyocytes also remains unclear. RESULTS: We show that PKAC interacts with CaV1.2α1 in heart and a heterologous model, independently of Rad, PKAR, or AKAPs. Studies with peptide array assays and purified recombinant proteins demonstrate direct binding of PKAC to two domains in CaV1.2α1-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Data indicate both partial competition and possible simultaneous interaction of PCRD and DCRD with PKAC. The βAR regulation of CaV1.2α1 lacking dCT (which harbors DCRD) was preserved, but subtly altered, in a heterologous model, the Xenopus oocyte. CONCLUSIONS: We discover direct interactions between PKAC and two domains in CaV1.2α1. We propose that these tripartite interactions, if present in vivo, may participate in organizing the multimolecular signaling complex and finetuning the βAR effect in cardiomyocytes. |
| Keywords: | Calcium Channel, Protein-Protein Interaction, Adrenergic Regulation, Cardiac, Protein Kinase A (PKA), Heterologous Express, Animals, Mice |
| Source: | BMC Biology |
| ISSN: | 1741-7007 |
| Publisher: | BioMed Central |
| Volume: | 22 |
| Number: | 1 |
| Page Range: | 276 |
| Date: | 28 November 2024 |
| Official Publication: | https://doi.org/10.1186/s12915-024-02076-9 |
| PubMed: | View item in PubMed |
Repository Staff Only: item control page
