title: Activation of M1 muscarinic receptors triggers transmitter release from rat sympathetic neurons through an inhibition of M-type K+ channels.
abstract: Acetylcholine has long been known to excite sympathetic neurons via M1 muscarinic receptors through an inhibition of M-currents. Nevertheless, it remained controversial whether activation of muscarinic receptors is also sufficient to trigger noradrenaline release from sympathetic neurons. In primary cultures of rat superior cervical ganglia, the muscarinic agonist oxotremorine M inhibited M-currents with half-maximal effects at 1 microM and induced the release of previously incorporated [3H]noradrenaline with half-maximal effects at 10 microM. This latter action was not affected by the nicotinic antagonist mecamylamine which, however, abolished currents through nicotinic receptors elicited by high oxotremorine M concentrations. Ablation of the signalling cascades linked to inhibitory G proteins by pertussis toxin potentiated the release stimulating effect of oxotremorine M, and the half-maximal concentration required to stimulate noradrenaline release was decreased to 3 microM. Pirenzepine antagonized the inhibition of M-currents and the induction of release by oxotremorine M with identical apparent affinity, and both effects were abolished by the muscarinic toxin 7. These results indicate that one muscarinic receptor subtype, namely M1, mediates these two effects. Retigabine, which enhances M-currents, abolished the release induced by oxotremorine M, but left electrically induced release unaltered. Moreover, retigabine shifted the voltage-dependent activation of M-currents by about 20 mV to more negative potentials and caused 20 mV hyperpolarisations of the membrane potential. In the absence of retigabine, oxotremorine M depolarised the neurons and elicited action potential discharges in 8 of 23 neurons; in its presence, oxotremorine M still caused equal depolarisations, but always failed to trigger action potentials. Action potential waveforms caused by current injection were not affected by retigabine. These results indicate that the inhibition of M-currents is the basis for the stimulation of transmitter release from sympathetic neurons via M1 muscarinic receptors.
authors.affiliation: Department of Pharmacology, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Lechner
authors.forename: Martina
authors.initials: M
authors.lastname: Mayer
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D005071:Evoked Potentials / Q000187:drug effects; D008464:Mecamylamine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism*; D010095:Oxotremorine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010655:Phenylenediamines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000187:drug effects / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D002219:Carbamates; D018721:Muscarinic Agonists; D010655:Phenylenediamines; D024642:Potassium Channels, Voltage-Gated; D043643:Receptor, Muscarinic M1; C101866:ezogabine; D013779:Tetrodotoxin; D010095:Oxotremorine; C042743:oxotremorine M; D008464:Mecamylamine; D037342:Pertussis Toxin; D009638:Norepinephrine