Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells.

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Abstract
The hypotensive diterpene, forskolin [from Coleus forskohlii; half-maximal effective concentration (EC50), 5-10 .mu.M] activates adenylate cyclase [ATP pyrophosphate-lyase (cyclizing)] in rat cerebral cortical membranes in a rapid and reversible manner. Activation is not dependent on exogenous guanyl nucleotides and is not inhibited by guanosine 5''-O-(2-thiodiphosphate) when assayed with adenosine 5''-[.beta.,.gamma.-imido]triphosphate as substrate. GTP and GDP potentiate responses for forskolin. The activations of adenylate cyclase by forskolin and guanosine 5''-[.beta.,.gamma.-imido]triphosphate, p[NH]ppG, are not additive, but activations by forskolin and F- are additive or partially additive. The responses of adenylate cyclase to forskolin or F- are not inhibited by Mn ions, but the response to p[NH]ppG is completely blocked. Activation of adenylate cyclase by forskolin is considerably greater than the activation by F- in membranes from rat cerebellum, striatum, heart and liver, while being about equal or less than the activation by F- in other tissues. Forskolin (EC50, 25 .mu.M) causes a rapid and readily reversible 35-fold elevation of cAMP in rat cerebral cortical slices that is not blocked by a variety of neurotransmitter antagonists. Low concentrations of forskolin (1 .mu.M) augment the response of cAMP-generating systems in brain slices to norepinephrine, isoproterenol, histamine, adenosine, prostaglandin E2 and vasoactive intestinal peptide. Forskolin may activate adenylate cyclase through a unique mechanism involving both direct activation of the enzyme and facilitation or potentiation of the modulation of enzyme activity by receptors or the guanyl nucleotide-binding subunit, or both.

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