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 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 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.

► α1-adrenergic signaling inhibits β-adrenergic signaling via tyrosine kinase.
► α1-adrenergic signaling inhibits β-adrenergically-activated contractile force.
► α1-adrenergic signaling inhibits β-adrenergically-activated L-type Ca2+ current.
► α1-adrenergic signaling phosphorylates tyrosine residues in β1-adrenoceptor.
► α1-signaling may serve as a feedback mechanism for preventing Ca2+ overload.