Forskolin alters acetylcholine receptor gating by a mechanism independent of adenylate cyclase activation

The diterpene forskolin activates adenylate cyclase in a receptor-independent fashion and is commonly used to obtain a rapid elevation of intracellular cAMP levels. Application of 10-20 microM forskolin to Xenopus oocytes that express Torpedo nicotinic acetylcholine (ACh) receptors leads to an acceleration in the decay of ACh-elicited currents, which could be taken as evidence for modulation of ACh receptor gating by cAMP-dependent protein kinase. However, the effect is not mimicked by phosphodiesterase inhibitors or intracellular injection of a cAMP analog. In addition, 1,9-dideoxyforskolin, which is unable to activate adenylate cyclase, has a similar effect. Finally, the action of forskolin is rapidly reversible, with full onset and recovery occurring within the exchange time of the recording chamber. These results suggest that forskolin is a potent local anesthetic and that this property of this widely used compound must be taken into account when using it to study ion channel modulation.