β-adrenoceptor control of g protein function in the neonate: Determinant of desensitization or sensitization
Neonatal β-adrenoceptors (β-ARs) are resistant to agonist-induced desensitization. We examined the functioning of Gi and G8 after repeated administration of β-AR agonists to newborn rats. Isoproterenol (β1/β2 agonist) obtunded Gi function in the heart but not the liver; in contrast, terbutaline, a β2-selective agonist, enhanced Gi function. Isoproterenol, but not terbutaline, increased membrane-associated Gsα, which would enhance receptor function. In addition, isoproterenol increased and terbutaline maintained the proportion of the short-splice (S) variant of Gsα in the membrane fraction; GsαS is functionally more active than the long-splice variant. Either isoproterenol or terbutaline treatment increased Gsα in the cytosolic fraction, a characteristic usually associated with desensitization in the adult. Decreased Gi activity, coupled with increased membrane-associated Gsα concentrations and maintenance or increases in membrane GsαS, provide strong evidence that unique effects on G protein function underlie the ability of the immature organism to sustain β-AR cell signaling in the face of excessive or prolonged stimulation; these mechanisms also contribute to tissue selectivity of the effects of β-agonists with divergent potencies toward different β-AR subtypes.
Auman, JT; Seidler, FJ; Slotkin, TA
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