Alpha1-adrenenoceptor stimulation inhibits cardiac excitation-contraction coupling through tyrosine phosphorylation of beta1-adrenoceptor

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 β(1)-adrenoceptor is estimated to regulate G(s)-protein binding affinity from crystal structure studies, but the signaling pathway leading to the phosphorylation of these residues is unknown. Here we show α(1)-adrenergic signaling inhibits b-adrenergically activated Ca(2+) current, Ca(2+) transients and contractile force through phosphorylation of tyrosine residues in β(1)-adrenoceptor by PTK. Our results indicate that inhibition of b-adrenoceptor-mediated Ca(2+) elevation by α(1)-adrenocep tor-PTK signaling serves as an important regulatory feedback mechanism when the catecholamine level increases to protect cardiomyocytes from cytosolic Ca(2+) overload.