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.
White
M M
MM
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000779:Anesthetics, Local; D000818:Animals; D003001:Cloning, Molecular; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D004553:Electric Conductivity; D004789:Enzyme Activation / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014101:Torpedo; D014982:Xenopus laevis
D000779:Anesthetics, Local; D007473:Ion Channels; D011978:Receptors, Nicotinic; D005576:Colforsin; D000262:Adenylyl Cyclases; C047983:1,9-dideoxyforskolin