Increased expression of G(s)α enhances activation of the adenylyl cyclase signal transduction cascade

Expression of the stimulatory G protein, G(s)α, can vary over a 3-fold range in human tissues and in rodent central nervous system. In fact, the offspring of alcoholics have higher levels of G(s)α expression in certain tissues compared with the offspring of nonalcoholics. The aim of this research was to test the hypothesis that a causal relationship exists between the level of expression of G(s)α and induction of the adenylyl cyclase (AC) cascade. The methodology employed transient transfection of HEK 293 cells with a cDNA for the 52-kDa form of G(s)α under regulation by inducible metallothionein promoters. Transfectants were exposed to varying concentrations (0-125 μM) of zinc sulfate that produced a 3-fold range of membrane G(s)α expression. The range of G(s)α expression produced was found to mimic a physiologically relevant spectrum of G(s)α expression in membranes derived from human tissues and rat brain. It was observed that induction of G(s)α expression increased constitutive as well as stimulated cAMP accumulation. Moreover, induction of G(s)α expression increased events distal to the accumulation of cAMP including the phosphorylation of the transcription factor, cAMP response element binding protein and transcriptional activation of cAMP-dependent reporter genes. In summary, these studies show that the amount of G(s)α expression has a marked impact on the level of activity of the AC cascade from the membrane through to the nucleus. It is hypothesized that individuals who differ in G(s)α expression may also differ in the expression of certain cAMP-dependent genes.