Adenosine suppresses protein kinase A‐ and C‐induced enhancement of glutamate release in the hippocampus

Cultured hippocampal neurons from neonatal rats were used to investigate the effect of adenosine on the release of glutamate. Spontaneous tetrodotoxin-resistant miniature excitatory postsynaptic currents (mEPSCs) through AMPA receptor channels were recorded by means of the whole-cell patch-clamp technique. Adenosine (50 microM) reversibly reduced the frequency of mEPSCs by approximately 50-60%, but did not change their amplitudes. The protein kinase A inhibitor Rp-cyclic adenosine monophosphate (100-150 microM) did not block the adenosine-dependent reduction of the mEPSC frequency, showing that adenosine is not depressing synaptic transmission via a protein kinase A (PKA)-dependent mechanism. The D1 dopamine agonist SKF-38393 (250 microM), forskolin (5 microM) and 8Br-cAMP (2 mM), known to activate the cAMP/PKA-dependent signalling pathway, all enhanced the mEPSC frequency. A subsequent application of adenosine (50 microM) strongly reduced the potentiation produced by any one of these three drugs. It also reversed protein kinase C (PKC)-dependent stimulation of glutamate release induced by phorbol myristate acetate (100 nM). Taken together, adenosine not only inhibits the spontaneous release of glutamate independently of protein kinases A and C but also reverses the enhancement of exocytosis produced by protein kinases A and C activators.