Synergy between membrane depolarization and muscarinic receptor activation leads to potentiation of neurotransmitter release (II)
Amplification of muscarinic agonist-induced [3H]noradrenaline ([3H]NE)-release by depolarizing agents, was studied in rat brain cortical slices. [3H]NE basal outflow was enhanced by either K+ (25 mM) or veratridine (2 microM) in a Ca2+-dependent manner and was potentiated beyond additivity in the presence of muscarinic agonists. Facilitation of the [3H]NE-induced release by the simultaneous presence of muscarinic agonists and depolarizing agents is calcium-dependent with a maximal effective concentration of 0.6-0.8 mM. The efficacy of muscarinic agonist to induce basal outflow of [3H]NE is as follows: CCh greater than arecoline greater than oxotremorine M greater than bethanechol greater than pilocarpine, which is similar to their potentiatory effects observed in the presence of depolarizing agents. Potentiation of muscarinic agonist-induced release of [3H]NE by elevated K+ is more pronounced (up to 7-fold) in comparison to potentiation by veratridine (up to 4-fold), irrespective of the various muscarinic agonists. The sequential presence of muscarinic agonists followed by depolarizing agents is not sufficient for eliciting a synergy of [3H]NE outflow, whether receptor activation was initiated prior to depolarization or depolarization was initiated prior to receptor activation. Receptors which do not mediate phosphatidyl inositol (PI) turnover such as nicotine induced [3H]NE-release which is not affected by the presence of depolarizing agents and yielded in their presence additive fractional release only. In this report we establish synergy of [3H]NE release by muscarinic agonists under depolarizing conditions, similar to synergism of inositol phosphate (IP) production which was observed by muscarinic agonists and depolarization agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Schwartz
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Department of Biological Chemistry, Hebrew University of Jerusalem, Israel.
Atlas
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D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009638:Norepinephrine / Q000493:pharmacokinetics*; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D014701:Veratridine / Q000494:pharmacology*; D014702:Veratrine / Q000031:analogs & derivatives*
D011976:Receptors, Muscarinic; D014701:Veratridine; D002217:Carbachol; D014702:Veratrine; D011188:Potassium; D009638:Norepinephrine