Forskolin stimulates adenylate cyclase in human colonic crypts: interaction with VIP

Forskolin in the 10(-8)-10(-4) M concentration range (ED50 2 microM) strongly stimulated the cyclic AMP production of epithelial crypts isolated from the human colon. At a maximal dose, production increased up to 500 and 700 times the basal cyclic AMP levels at 15 and 37 degrees C, respectively. Forskolin was thus much more efficient than VIP, which is the physiological regulator of this system. Forskolin (ED50 7 microM) also stimulated colonic membrane adenylate cyclase. The stimulation was immediate, did not require guanyl nucleotides and was inhibited by calcium (10(-5)-10(-3) M). In the concentration range between 10(-9) and 10(-5) M (ED50 0.04 microM), forskolin strongly potentiated the stimulation of adenylate cyclase by VIP. We conclude that: (1) forskolin exerts a double dose-dependent action on cyclic AMP production in human colonic crypts, i.e. direct activation of basal adenylate cyclase activity and potentiation of VIP effect; (2) forskolin may be a unique pharmacological tool to investigate the cyclic AMP-dependent processes in human intestine.