Altered cAMP-mediated signalling and its role in the pathogenesis of dilated cardiomyopathy.
Alterations in the level and function of proteins involved in cAMP-mediated signalling are important in the pathophysiology and treatment of dilated cardiomyopathy. What is unclear is the extent to which these alterations, which attenuate receptor-stimulated cAMP generation, contribute to the pathogenesis of dilated cardiomyopathy and the extent to which they constitute a beneficial compensatory response. Studies in animals involving overexpression and ablation of proteins or peptides involved in cAMP-mediated signalling have yielded disparate results that are difficult to reconcile with a simple hypothesis. Our ability to understand these differences is limited by the lack of information on how these different genetic manipulations affect the phosphorylation of individual substrates of protein kinase A (PK-A) through which cAMP signals are transduced. This is important in view of evidence that the phosphorylation of individual PK-A substrates can be regulated selectively in different intracellular compartments, and that the phosphorylation of some PK-A substrates is increased in dilated cardiomyopathy while the phosphorylation of others is reduced. Approaches that quantify changes in the phosphorylation of individual PK-A substrates in models of dilated cardiomyopathy will provide information that may allow a better understanding of the pathogenesis of the syndrome and a more rational approach to its treatment.
Movsesian
Matthew A
MA
Cardiology Section, VA Salt Lake City Health Care System, Department of Internal Medicine (Cardiology), University of Utah, 500 Foothill Boulevard, Salt Lake City, UT 84148, USA. matthew.movsesian@hsc.utah.edu
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases