Ontogeny of G-protein expression: control by beta-adrenoceptors

Cardiac cell homeostasis is maintained in the face of excessive beta-adreno ceptor stimulation through the process of desensitization, Desensitization is not an inherent property of these cells but rather is acquired during de velopment; neonates given beta-agonists actually show heterologous sensitiz ation, involving changes in the expression and catalytic activity of adenyl yl cyclase (AC) as well as an increased receptor/G-protein coupling. The cu rrent study examines the role of specific G-protein components, G(s alpha) and G(i alpha), in the ontogeny of beta-adrenoceptor responses and in the t ransition from agonist-induced sensitization to desensitization. Between po stnatal days (PN) 6 and 15 there was a significant decrease in the 52 kDa i soform of G(s alpha) with no accompanying change of the 45 kDa form; over t he same period, G(i alpha 3) also declined substantially. In contrast, the 45 kDa isoform of G(s alpha) and G(i alpha 1,2) remained fairly constant ov er the same period and fluoride-stimulated AC activity increased. Treatment with isoproterenol on PN2-5 did not result in any significant changes in G (s alpha) expression but robustly decreased G(i alpha 1,2). These changes w ere accompanied by heterologous sensitization of AC activity at the level o f AC itself, evidenced by equivalent increases in the enzymatic response to fluoride and forskolin-Mn2+. Isoproterenol given to older animals (PN11-14 ) also caused specific loss of G(i) protein, in this case targeting G(i alp ha 3) whereas G(s alpha) again was unchanged; in contrast to the younger gr oup, the older animals displayed heterologous desensitization of AC at the level of G-protein function (specific loss of the fluoride response). These results indicate that the normal ontogenetic increase of cardiac beta-adre noceptor coupling to AC is not dependent on the absolute amount of G-protei ns, nor on the relative balance of stimulatory (G(s)) and inhibitory (G(i)) subunits. However, the ability of receptor stimulation to downregulate G(i alpha 1,2), an event which is specific to immature cardiac cells, is likel y to be an important component of the resistance of the fetal/neonatal hear t to agonist-induced desensitization and hypertrophy. The maintenance of ca rdiac beta-adrenoceptor signaling in the face of intense stimulation is lik ely to play an important role in the physiologic adaptations necessary to t he perinatal transition. (C) 2000 Elsevier Science B.V. All rights reserved .