Adenosine activating A(2A)-receptors coupled to adenylate cyclase/cyclic AMP pathway downregulates nicotinic autoreceptor function at the rat myenteric nerve terminals

• Type: Article in International Scientific Journal
• Date: 2004

Authors

Margarida Araújo (Author) ICBAS; Timoteo, MA (Author) Other; Paulo Correia de Sá (Author) ICBAS

Journal

Title: Neurochemistry International

Vol. 45

Pages: 641-651

ISSN: 0197-0186

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 13 Citations

Scopus - 14 Citations

Other information

Authenticus ID: P-000-8CK

DOI: 10.1016/j.neuint.2004.03.027

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11