title: Alpha1-adrenenoceptor stimulation inhibits cardiac excitation-contraction coupling through tyrosine phosphorylation of beta1-adrenoceptor.
abstract: Adrenoceptor stimulation is a key determinant of cardiac excitation-contraction coupling mainly through the activation of serine/threonine kinases. However, little is known about the role of protein tyrosine kinases (PTKs) activated by adrenergic signaling on cardiac excitation-contraction coupling. A cytoplasmic tyrosine residue in β1-adrenoceptor is estimated to regulate Gs-protein binding affinity from crystal structure studies, but the signaling pathway leading to the phosphorylation of these residues is unknown. Here we show α1-adrenergic signaling inhibits β-adrenergically activated Ca(2+) current, Ca(2+) transients and contractile force through phosphorylation of tyrosine residues in β1-adrenoceptor by PTK. Our results indicate that inhibition of β-adrenoceptor-mediated Ca(2+) elevation by α1-adrenoceptor-PTK signaling serves as an important regulatory feedback mechanism when the catecholamine level increases to protect cardiomyocytes from cytosolic Ca(2+) overload.
authors: Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. O-Uchi@jikei.ac.jp
authors: Jin
authors: J
authors: O-Uchi
authors: Kimiaki
authors: K
authors: Komukai
authors: Yoichiro
authors: Y
authors: Kusakari
authors: Satoshi
authors: S
authors: Morimoto
authors: Makoto
authors: M
authors: Kawai
authors: Bong Sook
authors: BS
authors: Jhun
authors: Stephen
authors: S
authors: Hurst
authors: Kenichi
authors: K
authors: Hongo
authors: Shey-Shing
authors: SS
authors: Sheu
authors: Satoshi
authors: S
authors: Kurihara
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D010656:Phenylephrine; D014443:Tyrosine; C026777:ICI 118551; D000262:Adenylyl Cyclases; D007545:Isoproterenol