Regulation of Depolarization-Dependent Release of Neurotransmitters by Adenosine: Cyclic AMP-Dependent Enhancement of Release from PC12 Cells

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Abstract
Pheochromocytoma cells, clone PC12 were used as a model system for studying the effects of adenosine on neurosecretion. Exposure of the cells to adenosine or 2-chloroadenosine caused immediate activation of adenylate cyclase, increases in cellular cAMP content, and inhibition of SAM-dependent [s-adenosylmethionine] phospholipid N-methylation and protein carboxymethylation. The effects on methylation were only observed with concentrations of adenosine 100 times greater than those that elevated cAMP. Exposure of the cells to adenosine and 2-chloroadenosine did not alter the release of [3H]norepinephrine ([3H]NE) in the absence of depolarization. Depolarization-dependent release of [3H]NE was markedly elevated by short (1-20 min) pretreatments with adenosine or 2-chloroadenosine. The enhancement of release was observed irrespective of the nature of the depolarizing stimulus (elevated K+, carbamylcholine, veratridine). Release of [3H]acetylcholine in response to elevated K+ also was increased by adenosine pretreatment. The effects of adenosine and 2-chloroadenosine on neurotransmitter release closely paralleled elevation of cellular cAMP but not inhibition of methylation. Adenosine, probably acting through adenosine receptors coupled to stimulation of adenylate cyclase, is able to modulate the neurosecretory process in PC12 cells. The enhancement of release occurred even though the extent of depolarization (measured as 86Rb+ flux through the acetylcholine receptor channel) and the amount of 45Ca2+ which entered upon depolarization were unchanged. The enhancement of release produced by elevated cAMP appeared to reflect increased efficiency of the stimulus-secretion coupling process.