β-Adrenergic Signal Transduction Pathway in Developing and Aging Hearts

Abstract

The β-adrenergic signal transduction pathway in the heart consists of three major components, namely β-adrenergic receptors, guanine nucleotide-binding proteins (G-proteins), and adenylyl cyclase.β-adrenergic receptors, which recognize and bind catecholamines in the myocardium, are primarily of two types: β1-adrenoceptors andβ2-adrenoceptors. Two major types of G-proteins, namely stimulatory (Gs) and inhibitory (Gi) proteins, are expressed in the heart. Although five isoforms of adenylyl cyclase have been detected in the heart, type Vand type VI are present in abundance. While β-adrenergic receptors are coupled to adenylyl cyclase through Gs-proteins, Gi-proteins are known to regulate the adenylyl cyclase activity. β-adrenergic receptors are regulated by β-adrenoceptor kinase and β-arrestin present in the myocardium. Although β-adrenoceptors have been detected in fetal heart, their coupling with Gs-proteins and adenylyl cyclase is weak during early embryonic and fetal life. β2-adrenoceptors, unlikeβ1-adrenoceptors, have been shown to play an important role in catecholamine action in neonatal hearts in comparison to the adult myocardium. Both types V and VI of adenylyl cyclase are expressed weakly in neonatal heart, but type V isoform is predominant in the adult heart. The attenuated responses of the aging heart to catecholamines are explained on the basis of depressed adenylyl cyclase and increased Gi-protein contents since no changes in β-adrenoceptors or Gs-proteins were seen in the aged myocardium. The status of different components of the β-adrenergicreceptor system in both fetal and aging hearts is considered to provide clues regarding defects in the signal transduction mechanisms in heart failure.