Abstract
S49 mouse lymphoma cells contain a beta-adrenergic receptor coupled to Gs that stimulates adenylyl cyclase and a somatostatin receptor coupled to Gi that inhibits adenylyl cyclase. Membranes from these cells were used to compare the inhibitory effects of somatostatin and G protein beta gamma complex to determine under what conditions beta gamma is likely to be a mediator of somatostatin action. Somatostatin was equally effective at inhibiting basal adenylyl cyclase activity in the presence of GTP, forskolin-stimulated activity, and hormone-stimulated activity. G protein beta gamma was more effective at inhibiting basal activity than was somatostatin, and these effects were partially additive. In the presence of forskolin, the two inhibitors were equally effective and not additive. In the presence of isoproterenol, beta gamma was much less effective than somatostatin, and the two inhibitors did not have additive or synergistic effects. At very high concentrations beta gamma did inhibit isoproterenol stimulation of adenylyl cyclase, although its effects were not saturating even at 100 micrograms/ml. Under conditions where beta gamma did inhibit hormone stimulation, beta gamma was a mixed inhibitor of isoproterenol stimulation, proportionally decreasing the maximum effect of the hormone and increasing the half-maximally effective concentration. Somatostatin, on the other hand, was a simple noncompetitive inhibitor of isoproterenol stimulation. These results indicate that beta gamma and somatostatin inhibit adenylyl cyclase by different mechanisms, at least in the presence of hormones that stimulate the enzyme. It is proposed that alpha i is the primary mediator of hormone inhibition of adenylyl cyclase when Gs is activated by a hormone, but that beta gamma may have a role as a mediator of inhibition of basal activity.
Highlights
An alternative proposal suggests that hormone inhibition of adenylyl cyclase results from a direct effect of 01,(23,24), analogous to the well demonstrated effects of 01~and at [5, 6]
G Protein @y Is Not the Mediator of Hormone Inhibition of Adenylyl Cyclase Stimulated by an Activated G,Isoproterenol activation of the S49 cell membrane adenylyl cyclase decreases its susceptibility to inhibition by G protein Pr (Figs. 3 and 4). Results analogous to this have been reported by others [9, 12]. Though, this effect of isoproterenol on @y-mediated inhibition was compared with its effect on hormone inhibition of adenylyl cyclase
Isoproterenol did not decrease either the potency or efficacy of somatostatin (Fig. 1) even though it decreased at least the potency of Pr for inhibition by l-2 orders of magnit.ude (Fig. 4)
Summary
Several studies support this role for the /3r complex [6,9, 12] This mechanism forms the basis for one proposal about how G proteins mediate hormone inhibition of adenylyl cyclase [13], whereby P-yderived from activated Gi, or perhaps other G proteins as well, blocks A previous study [13] showed that in the presence of forskolin, somatostatin and /3r have equivalent and nonadditive inhibitory effects on adenylyl cyclase activity; evidence supported fir as the mediator of somatostatin action. Under conditions where /3r does inhibit hormonestimulated adenylyl cyclase, inhibition by somatostatin and /3r are kinetically different These results indicate that fir and somatostatin inhibit adenylyl cyclase by different mechanisms, at least in the presence of hormones that stimulate the enzyme
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