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 β₁-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 α₁-adrenergic signaling inhibits β-adrenergically activated Ca²⁺ current, Ca²⁺ transients and contractile force through phosphorylation of tyrosine residues in β₁-adrenoceptor by PTK. Our results indicate that inhibition of β-adrenoceptor-mediated Ca²⁺ elevation by α₁-adrenoceptor-PTK signaling serves as an important regulatory feedback mechanism when the catecholamine level increases to protect cardiomyocytes from cytosolic Ca²⁺ overload.