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
.