Direct anesthetic-like effects of forskolin on the nicotinic acetylcholine receptors of PC12 cells

Forskolin is thought to be a highly specific activator of adenyl cyclase. However, when applied to rat pheochromocytoma (PC12) cells at concentrations of 1 μM or higher it caused an immediate, concentration-dependent inhibition of carbachol-stimulated uptake of ⁸⁶Rb⁺ through the nicotinic receptors, which did not appear to be related to activation of adenyl cyclase. The inhibition of receptor activation occurred instantaneously whereas cellular cAMP content did not increase for a measurable period of time. Normal receptor function was recovered rapidly upon removal of forskolin. Additional evidence that this effect of forskolin was not related to cAMP was obtained when 1,9-dideoxyforskolin (an analog of forskolin which does not activate adenyl cyclase) also caused a rapid, concentration-dependent, rapidly reversible inhibition of receptor-mediated influx of ⁸⁶Rb⁺ into the cells. An examination of the effect of forskolin on ⁸⁶Rb⁺ uptake at various concentrations of carbachol showed that forskolin was not acting by competing with carbachol for the receptor activation site. Given the lipophilic nature of forskolin, it probably acts like a general anesthetic to perturb the plasma membrane lipid structure and alter the function of the nicotinic acetylcholine receptors, possibly by increasing the rate of closure of open channels.