title: Glucocorticoid modulation of protein phosphorylation and sarcoplasmic reticulum function in rat myocardium.
abstract: To decipher the mechanism(s) underlying glucocorticoid action on cardiac contractile function, this study investigated the effects of adrenalectomy and dexamethasone treatment on the contents of sarcoplasmic reticulum (SR) Ca(2+)-cycling proteins, their phosphorylation by endogenous Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II), and SR Ca(2+) sequestration in the rat myocardium. Cardiac SR vesicles from adrenalectomized rats displayed significantly diminished rates of ATP-energized Ca(2+) uptake in vitro compared with cardiac SR vesicles from control rats; in vivo administration of dexamethasone to adrenalectomized rats prevented the decline in SR function. Western immunoblotting analysis showed that the relative protein amounts of ryanodine receptor/Ca(2+)-release channel, Ca(2+)-ATPase, calsequestrin, and phospholamban were neither diminished significantly by adrenalectomy nor elevated by dexamethasone treatment. However, the relative amount of SR-associated CaM kinase II protein was increased 2.5- to 4-fold in dexamethasone-treated rats compared with control and adrenalectomized rats. Endogenous CaM kinase II activity, as judged from phosphorylation of ryanodine receptor, Ca(2+)-ATPase, and phospholamban protein, was also significantly higher (50--80% increase) in the dexamethasone-treated rats. The stimulatory effect of CaM kinase II activation on Ca(2+) uptake activity of SR was significantly depressed after adrenalectomy and greatly enhanced after dexamethasone treatment. These findings identify the SR as a major target for glucocorticoid actions in the heart and implicate modification of the SR CaM kinase II system as a component of the mechanisms by which dexamethasone influences SR Ca(2+)-cycling and myocardial contraction.
authors.affiliation: Department of Physiology, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: M K
authors.initials: MK
authors.lastname: Rao
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.forename: N
authors.initials: N
authors.lastname: Narayanan
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004734:Energy Metabolism; D004789:Enzyme Activation / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D011506:Proteins; D003907:Dexamethasone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000252:Calcium-Transporting ATPases; D002118:Calcium