Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 45, Issue 5, Pages 641-651Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2004.03.027
Keywords
nicotinic autoreceptor; adenosine A(2A) receptor; cyclic AMP; cholinergic nerve terminals; acetylcholine release; myenteric plexus
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In addition to the somatodendritic region, myenteric motoneuron terminals are endowed with nicotinic autoreceptors. We aimed at investigating the effect of nicotinic receptor (nAChR) activation on [H-3]-acetylcholine ([H-3]-ACh) release from longitudinal muscle-myenteric plexus of the rat ileum and to evaluate whether this could be modulated by adenosine, an endogenous neuromodulator typically operating changes in intracellular cyclic AMP. The nAChR agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP, 1-30 muM, 3 min) increased [H-3]-ACh release in a concentration-dependent manner. DMPP (30 muM)-induced [H-3]-ACh outflow was attenuated by hexamethonium (0.1-1 mM), tubocurarine (1-5 muM), or by removing external Ca2+ (plus EGTA, 1 mM). In contrast to veratridine (0.2-10 muM)-induced [H-3]-ACh release, the DMPP (30 muM)-induced outflow was resistant to tetrodotoxin (1 muM) and cadmium (0.5 mM). Pretreatment with adenosine deaminase (0.5 U/mL) or with the adenosine A(2A)-receptor antagonist, ZM 241385 (50 nM), enhanced nAChR-induced transmitter release. Activation of A(2A) receptors with CGS 21680C (3 nM) reduced the DMPP-induced release of [H-3]-ACh. CGS 21680C (3 nM) inhibition was prevented by MDL 12,330A (10 muM, an adenylate cyclase inhibitor) and by H-89 (10 muM, an inhibitor of protein kinase A), but was potentiated by rolipram (300 muM, a phosphodiesterase inhibitor). DMPP-induced transmitter release was decreased by 8-bromo-cyclic AMP (1 mM, a protein kinase A activator), rolipram (300 muM), and forskolin (3 muM, an activator of adenylate cyclase). Both MDL 12,330A (10 muM) and H-89 (10 muM) facilitated DMPP-induced release of [H-3]-ACh. The results indicate that nAChR-induced [H-3]-ACh release is triggered by the influx of Ca2+, independent of voltage-sensitive calcium channels, presumably directly through nAChRs located on myenteric axon terminals. It was also shown that endogenous adenosine, activating A(2A) receptors coupled to the adenylate cyclase/cyclic AMP transducing system, is tonically downregulating this nAChR-mediated control of [H-3]-ACh release. (C) 2004 Elsevier Ltd. All rights reserved.
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