Interactions between the Regulatory Subunit of Type I Protein Kinase A (PKARIalpha) and p90 Ribosomal S6 Kinase1 (RSK1) Regulate Cardiomyocyte Apoptosis Journal Article

Authors: Gao, X; Lin, B.; Sadayappan, S; Patel, T. B.
Article Title: Interactions between the Regulatory Subunit of Type I Protein Kinase A (PKARIalpha) and p90 Ribosomal S6 Kinase1 (RSK1) Regulate Cardiomyocyte Apoptosis
Abstract: Cardiomyocyte apoptosis contributes toward loss of muscle mass in myocardial pathologies. Previous reports have implicated type I cAMP-dependent protein kinase (PKA) and p90 ribosomal S6 kinase (RSK) in cardiomyocyte apoptosis. However, the precise mechanisms and the isoform of RSK involved in this process remain undefined. Using adult rat ventricular myocytes (ARVMs) and mouse- derived HL-1 cardiomyocytes, we demonstrate that hypoxia/re-oxygenation (H/R) induced apoptosis is accompanied by a decrease in the type I PKA regulatory subunit (PKARIalpha) and activation of RSK1. As previously described by us in other cell types, in cardiomyocytes inactive RSK1 also interacts with PKARIalpha while the active RSK1 interacts with the catalytic subunit of PKA (PKAc). Additionally, siRNA- mediated silencing of PKARIalpha or disrupting the RSK1/PKARIalpha interactions with a small, cell permeable peptide activates RSK1 and recapitulates the H/R- induced apoptosis. Inhibition of RSK1 or siRNA- mediated silencing of RSK1 attenuate H/R- induced apoptosis, demonstrating the role of RSK1 in cardiomyocyte apoptosis. Furthermore, silencing of RSK1 decreases the H/R- induced phosphorylation of sodium-hydrogen exchanger 1 (NHE1), and inhibition of NHE1 with EIPA blocks H/R induced apoptosis, indicating the involvement of NHE1 in apoptosis. Over all, our findings demonstrate that H/R- mediated decrease in PKARIalpha protein levels lead to activation of RSK1, which via phosphorylation of NHE1 induces cardiomyocyte apoptosis.
Keywords: Animals; Mice; Rats; Phosphorylation; apoptosis; Cells, Cultured; Cation Transport Proteins/metabolism; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/physiology; Myocytes, Cardiac/enzymology/physiology; Ribosomal Protein S6 Kinases, 90-kDa/physiology; Sodium-Hydrogen Antiporter/metabolism
Journal Title: Molecular pharmacology
Volume: 85
Issue: 2
ISSN: 1521-0111; 0026-895X
Publisher: Unknown  
Date Published: 2014
Start Page: 357
End Page: 367
Language: ENG
Notes: LR: 20150203; GR: K02-HL114749/HL/NHLBI NIH HHS/United States; GR: R01-GM079226/GM/NIGMS NIH HHS/United States; GR: R01-HL105826/HL/NHLBI NIH HHS/United States; JID: 0035623; 0 (Cation Transport Proteins); 0 (Cyclic AMP-Dependent Protein Kinase RIalpha Subunit); 0 (Slc9a1 protein, mouse); 0 (Sodium-Hydrogen Antiporter); EC (Ribosomal Protein S6 Kinases, 90-kDa); OID: NLM: PMC3913359; 2013/12/04 [aheadofprint]; ppublish