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Increased Expression Of G_s Enhances Activation Of The Adenylyl Cyclase Signal Transduction Cascade

Departments of Medicine and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Expression of the stimulatory G protein, G_s, 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 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 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 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 expression. The range of G_s expression produced was found to mimic a physiologically relevant spectrum of G_s expression in membranes derived from human tissues and rat brain. It was observed that induction of G_s expression increased constitutive as well as stimulated cAMP accumulation. Moreover, induction of G_s 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 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 expression may also differ in the expression of certain cAMP-dependent genes.

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