Evidence suggests that both α and βγ subunits of heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins) inhibit adenylyl cyclase. Although type I adenylyl cyclase is inhibited directly by exogenous βγ, inhibition of adenylyl cyclase by G iα has not been convincingly demonstrated in vitro. Concentration-dependent inhibition of adenylyl cyclases by purified G iα subunits is described. Activated Giα but not Goα was effective, and myristoylation of G iα was required. The characteristics of the inhibitory effect were dependent on the type of adenylyl cyclase and the nature of the activator of the enzyme. The concentrations of Giα required to inhibit adenylyl cyclase were substantially higher than those normally thought to be relevant physiologically. However, analysis indicates that these concentrations may be relevant and reasonable.
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