Pharmacological elevation of cyclic AMP and transmitter release at the mouse neuromuscular junction.
Intracellular recordings of spontaneous and evoked end-plate potentials have been made at the neuromuscular junction of mouse hemidiaphragms to determine a possible role of cyclic AMP (cAMP) in the release of acetylcholine from presynaptic terminals. Spontaneous release, as determined from the frequency of miniature end-plate potentials, was increased by drugs that inhibit phosphodiesterase: isobutylmethylxanthine (IBMX), SQ 20,009, theophylline, and caffeine; drugs that stimulate adenylate cyclase: forskolin, fluoride, and cholera toxin, and the stable analogue of cAMP: 8-bromo-cAMP but not dibutyryl cAMP. Release increased with time during maintained exposure to the drugs and generally followed a simple exponential time course with time constants ranging from 8 to 17 min at 20 degrees C, except for SQ 20,009 and cholera toxin which required longer exposure times for effect. The order of potency of the phosphodiesterase inhibitors was IBMX = SQ 20,009 greater than theophylline = caffeine. This is consistent with an effect mediated by an increase in cAMP concentrations within the nerve terminal. Evoked release, determined from the quantal content of the end-plate potential, was increased to a lesser extent than spontaneous release. The results are discussed with reference to the possible involvement of second messengers in the release of vesicles from nerve terminals in vertebrate synapses.
Dryden
W F
WF
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Singh
Y N
YN
Gordon
T
T
Lazarenko
G
G
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D005071:Evoked Potentials / Q000187:drug effects; D005459:Fluorides / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology
D018377:Neurotransmitter Agents; D010726:Phosphodiesterase Inhibitors; D005576:Colforsin; D002110:Caffeine; D002772:Cholera Toxin; D013806:Theophylline; D000242:Cyclic AMP; D005459:Fluorides; D015056:1-Methyl-3-isobutylxanthine