cAMP-mediated signal transduction and sarcoplasmic reticulum function in heart failure.
There is evidence that the effects of beta-adrenergic receptor agonists on myocardial contractility result principally from the phosphorylation of phospholamban by cAMP-dependent protein kinase and the consequent deinhibition of SERCA2 activity and stimulation of sarcoplasmic reticulum Ca2+ transport. An impairment in beta-adrenergic receptor-stimulated cAMP generation, attributable to down-regulation of beta 1-adrenergic receptors and increased activity of G alpha i and G protein-coupled receptor kinase, has long been recognized in failing human myocardium. This impairment is associated with a compartment-specific decrease in sarcoplasmic reticulum cAMP content that may selectively reduce phospholamban phosphorylation. Published and preliminary results indicate that two plausible explanations for this compartment-specific decrease--a reduction in sarcoplasmic reticulum-associated cAMP-dependent protein kinase or an increase in sarcoplasmic reticulum-associated cAMP phosphodiesterase--are unlikely. Instead, there is reason to believe that the selective reduction in beta 1-adrenergic receptor density in failing myocardium is causally related to this compartment-specific decrease in cAMP content through an as-yet-undetermined mechanism. The fact that the modulation of SERCA2 activity by phospholamban is preserved in failing human myocardium offers an opportunity for improvement in the therapy of heart failure.
Movsesian
M A
MA
Salt Lake City VA Medical Center, Utah, USA. matthew.movsesian@hsc.utah.edu
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D000252:Calcium-Transporting ATPases; D002118:Calcium