title: Beta-adrenergic regulation of a myocardial actin gene via a cyclic AMP-independent pathway.
abstract: The skeletal alpha-actin gene encodes a major component of the embryonic cardiac sarcomere that is strongly and selectively re-induced during beta-adrenoceptor-mediated hypertrophy in neonatal rat cardiac myocytes. We present evidence that beta-adrenergic induction of this gene is mediated, not by cAMP, but by a calcium-dependent pathway involving ryanodine-sensitive calcium stores. Nifedipine-induced blockade of the plasma membrane L-type calcium entry channel prevented induction of skeletal alpha-actin mRNA by isoproterenol. Activation of calcium entry by the dihydropyridine agonist Bay K8644 independently induced skeletal alpha-actin mRNA, as did cholera toxin-mediated activation of Gs. Induction of skeletal alpha-actin mRNA by compounds that directly elevate cAMP was weak relative to their effects on other cAMP-dependent phenomena and required calcium entry. In addition, selective inhibition of protein kinase A with KT5720 did not block beta-adrenergic induction of skeletal alpha-actin. Calcium ionophore A23187 did not induce skeletal actin, but prevented its induction by isoproterenol. Ryanodine had bimodal effects: 10(-10) M ryanodine induced skeletal alpha-actin mRNA, whereas 10(-6) M ryanodine prevented skeletal actin induction by beta-adrenergic stimuli. We postulate that beta-adrenergic stimulation of skeletal alpha-actin mRNA requires G-protein-coupled calcium channel activation and compartmentalized calcium release in a manner independent of the cAMP/protein kinase A signal pathway.
authors.affiliation: Department of Veterans Affairs Medical Center, Cardiovascular Research Institute, San Francisco, California.
authors.forename: N H
authors.initials: NH
authors.lastname: Bishopric
authors.forename: B
authors.initials: B
authors.lastname: Sato
authors.forename: K A
authors.initials: KA
authors.lastname: Webster
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000199:Actins / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D003994:Bucladesine / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics; D012313:RNA / Q000187:drug effects / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology
chemical_list: D000199:Actins; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; C029992:proenkephalin; D012433:Ryanodine; D005576:Colforsin; D000001:Calcimycin; D002110:Caffeine; D012313:RNA; D003994:Bucladesine; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011433:Propranolol; D000242:Cyclic AMP; D009543:Nifedipine; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine