Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K–AKT–nNOS signaling
| Autor: | Sandor Gyorke, Stephen Baine, Rengasayee Veeraraghavan, Ingrid M. Bonilla, Przemysław B. Radwański, Marina S. Ivanova, Justin Thomas, Cynthia A. Carnes, Jiaoni Li, Andriy E. Belevych |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Nitric Oxide Synthase Type I
Biochemistry Ryanodine receptor 2 Phosphatidylinositol 3-Kinases Cyclic GMP-Dependent Protein Kinases Animals Myocytes Cardiac Phosphorylation Molecular Biology Protein kinase B Cells Cultured biology Chemistry Kinase Ryanodine receptor Ryanodine Receptor Calcium Release Channel Cell Biology Cell biology Mice Inbred C57BL Nitric oxide synthase cardiovascular system biology.protein Signal transduction Proto-Oncogene Proteins c-akt cGMP-dependent protein kinase Signal Transduction |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| Popis: | Post-translational modifications of proteins involved in calcium handling in myocytes, such as the cardiac ryanodine receptor (RyR2), critically regulate cardiac contractility. Recent studies have suggested that phosphorylation of RyR2 by protein kinase G (PKG) might contribute to the cardioprotective effects of cholinergic stimulation. However, the specific mechanisms underlying these effects remain unclear. Here, using murine ventricular myocytes, immunoblotting, proximity ligation as-says, and nitric oxide imaging, we report that phosphorylation of Ser-2808 in RyR2 induced by the muscarinic receptor agonist carbachol is mediated by a signaling axis comprising phosphoinositide 3-phosphate kinase, Akt Ser/Thr kinase, nitric oxide synthase 1, nitric oxide, soluble guanylate cyclase, cyclic GMP (cGMP), and PKG. We found that this signaling pathway is compartmentalized in myocytes, as it was distinct from atrial natriuretic peptide receptor–cGMP–PKG–RyR2 Ser-2808 signaling and independent of muscarinic-induced phosphorylation of Ser-239 in vasodilator-stimulated phosphoprotein. These results provide detailed insights into muscarinic-induced PKG signaling and the mediators that regulate cardiac RyR2 phosphorylation critical for cardiovascular function. |
| Databáze: | OpenAIRE |
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