Adenosine A2receptor‐mediated excitation of a subset of AH/Type 2 neurons and elevation of cAMP levels in myenteric ganglia of guinea‐pig ileum

AbstractThe aim of the study was to test the hypothesis that excitatory A2and inhibitory A1receptors coexist on myenteric AHIType 2 neurons, and are positively coupled to adenylate cyclase to stimulate cAMP formation. The A2agonists NECA and CGS 21680 increased excitability and depolarized the membrane in 40% of 71 AH/Type 2 neurons. In the remainder, the agonists depressed excitability and hyperpolarized the neurons. In 13% of neurons, A2agonists caused a concentration‐dependent depolarization at nanomolar concentrations, followed by hyperpolarization at higher concentrations. CGS 21680 (EC50=0.15 nM) was 133‐fold more potent than NECA (EC50= 20 nM) in depolarizing AH/Type 2 neurons. The A1agonist, CCPA, caused hyperpolarization and depressed excitability in more than 90% of neurons. The potency profile of agonists for depolarization was CGS 21680 ≫ NECA ≫> CCPA. NECA augmented at nanomolar and inhibited at micromolar concentrations, excitatory depolarizing responses to forskolin in AH/Type 2 neurons; whereas, CCPA only inhibited the action of forskolin. In parallel studies on enzymatically dissociated myenteric ganglia, when the ganglia were exposed to priming concentrations of forskolin (5 μM) in the presence of Ro‐20 1724, NECA enhanced the stimulatory action of forskolin on CAMP formation. This effect was abolished by the adenosine receptor antagonist DPSPX. The potency of NECA for stimulation of adenylate cyclase equalled that for depolarization of the AH/Type 2 neurons. The results suggest that high affinity excitutory A2receptors are coupled to adenylate cyclase in a minority subset of AH/Type 2 myenteric neurons, and that inhibitory A1and excitatory A2receptors are co‐localized on some AH/Type 2 neurons.