Alpha1-adrenergic receptors activate AKT via a Pyk2/PDK-1 pathway that is tonically inhibited by novel protein kinase C isoforms in cardiomyocytes.
AKT is a potent antiapoptotic kinase, but its role in the cardioprotective actions of alpha(1)-adrenergic receptors (ARs) remains uncertain, because alpha(1)-ARs typically induce little-to-no AKT activation in most cardiomyocyte models. This study identifies a prominent alpha(1)-AR-dependent AKT activation pathway that is under tonic inhibitory control by novel protein kinase Cs (nPKCs) in neonatal rat cardiomyocyte cultures. We also implicate Pyk2, Pyk2 complex formation with PDK-1 and paxillin, and increased PDK-1-Y373/376 phosphorylation as the mechanism that links alpha(1)-AR activation to increased AKT phosphorylation. nPKCs (which are prominent alpha(1)-AR effectors) interfere with this alpha(1)-AR-dependent AKT activation by blocking Pyk2/PDK-1/paxillin complex formation and PDK-1-Y373/376 phosphorylation. Additional studies used an adenoviral-mediated overexpression strategy to show that Pyk2 exerts dual controls on antiapoptotic PDK-1/AKT and proapoptotic c-Jun N-terminal kinase (JNK) pathways. Although the high nPKC activity of most cardiomyocyte models favors Pyk2 signaling to JNK (and cardiac apoptosis), the cardioprotective actions of Pyk2 through the PDK-1/AKT pathway are exposed when PKC or JNK activation is prevented. Collectively, these studies identify JNK and AKT as functionally distinct downstream components of the alpha(1)-AR/Pyk2 signaling pathway. We also implicate nPKCs as molecular switches that control the balance of signaling via proapoptotic JNK and antiapoptotic PDK-1/AKT pathways, exposing a novel mechanism for nPKC-dependent regulation of cardiac hypertrophy and failure.
Guo
Jianfen
J
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W 168th St, New York, NY 10032, USA.
Sabri
Abdelkarim
A
Elouardighi
Hasnae
H
Rybin
Vitalyi
V
Steinberg
Susan F
SF
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000166:cytology; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D051419:Paxillin; C496063:Pxn protein, rat; D018340:Receptors, Adrenergic, alpha-1; D011494:Protein Kinases; C089212:protein kinase D; D051418:Focal Adhesion Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; C070515:bisindolylmaleimide I