Desensitization of acetylcholine receptors in rat myotubes is enhanced by agents that elevate intracellular cAMP.
Incubating skeletal muscle fibers with forskolin, an activator of adenylate cyclase, increases the rate at which nicotinic acetylcholine receptors (AChRs) desensitize when exposed to ACh. Several reports indicate that this is due to the phosphorylation of AChRs by cAMP-dependent protein kinase, but other studies suggest that forskolin interacts with AChRs directly and that second-messenger systems are not required. To help clarify this issue, we studied the effects of forskolin and several other drugs on AChR function in embryonic rat myotubes. AChR function was studied by recording ACh-induced membrane depolarizations and ACh-induced single-channel currents. Our results indicate that forskolin at low concentrations enhances AChR desensitization through the action of a second messenger, most likely cAMP. An analog of forskolin that is much less effective in activating adenylate cyclase (1,9-dideoxyforskolin) is also much less potent in enhancing desensitization. Forskolin at low concentrations does not alter single-channel conductance or mean channel open time. However, when used at concentrations above 20 microM, forskolin may also exert direct drug effects on AChRs.
Middleton
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P
Columbia University, Department of Biological Sciences, New York, New York 10027.
Rubin
L L
LL
Schuetze
S M
SM
D000818:Animals; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism*; D007473:Ion Channels / Q000187:drug effects; D009132:Muscles / Q000378:metabolism*; D051381:Rats; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism*
D007473:Ion Channels; D011950:Receptors, Cholinergic; D005576:Colforsin; D000242:Cyclic AMP