Adenosine A1‐receptor‐mediated inhibition of evoked acetylcholine release in the rat hippocampus does not depend on protein kinase C

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Abstract
The possible involvement of protein kinase C and/or a lipoxygenase product in the mechanism by which adenosine inhibits release of [3H]acetylcholine evoked by electrical pulses from [3H]choline‐labelled hippocampal slices was examined. For comparison, the muscarinic autoreceptors were examined using carbachol. The order of potency of adenosine analogues (CHA = R‐PIA > NECA± CGS 21680, CV 1808) indicates that the adenosine receptor responsible is of the A1subtype. Adenosine (10 μM) and R‐PIA (0.1 μm) were virtually equiactive as inhibitors and were antagonized to an equal extent by 8–CPT with a potency (IC50approximately 25 nm) which is also compatible with A1‐receptor mediation. The effects of carbachol and of R‐PIA were not antagonized by the lipoxygenase inhibitor NDGA (10 or 50 μm). Stimulation of protein kinase C by the phorbol ester 4β‐phorbol 12, 13–dibutyrate caused a concentration‐dependent increase in stimulation‐evoked3H overflow, but did not antagonize the presynaptic inhibitory effect of R‐PIA or carbachol (0.01–1 μm). Staurosporine (0.1 μm), which inhibited the stimulating effect of phorbol dibutyrate, did not alter the effects of carbachol or R‐PIA. The presynaptic effects of phorbol dibutyrate, R‐PIA and adenosine were reduced by pretreatment withN‐ethylmaleimide (100, μ M for 10 min), which inactivates G‐proteins. The evoked transmitter release was unaffected by nifedipine (1 μ M) in the presence and in the absence of phorbol dibutyrate.These results indicate that adenosine, by acting at presynaptic A,‐receptors, reduces transmitter release by a mechanism that involves neither an NDGA‐sensitive lipoxygenase nor protein kinase C. The results also indicate that the enhancement of transmitter release by phorbol esters is due to protein kinase C activation and that a G‐protein may be involved in the effect but a dihydropyridine‐sensitive L‐type Ca2+channel probably is not.

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