C-Jun N-terminal kinase regulates adenosine A1 receptor-mediated synaptic depression in the rat hippocampus.

Adenosine A1 receptors are ubiquitous mediators of presynaptic inhibition of neurotransmission in the central nervous system, yet the signalling pathway linking A1 receptor activation and decreased neurotransmitter release remains poorly resolved. We tested the contribution of c-Jun N-terminal kinase (JNK) to adenosine A1 receptor-mediated depression of field excitatory postsynaptic potentials (fEPSPs) in area CA1 of the rat hippocampus. We found that inhibition of JNK with SP600125 or JNK inhibitor V, but not an inactive analogue, attenuated the depression of fEPSPs induced by adenosine, hypoxia, and the A1 receptor agonist N(6)-cyclopentyladenosine (CPA). In contrast, the JNK inhibitor SP600125 did not inhibit GABA(B)-mediated synaptic depression. In support of our electrophysiological findings, Western blot analysis showed that A1 receptor stimulation resulted in a transient increase in JNK phosphorylation in the membrane fraction of hippocampal lysates. The total amount of JNK in the membrane fraction was unchanged by CPA treatment. The increase in phosphorylated JNK induced by A1 receptor stimulation was blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), indicating that A1 receptors specifically activate JNK in the hippocampus. Together with functional data indicating that JNK inhibition decreased CPA-induced paired pulse facilitation, these results suggest that JNK activation is necessary for adenosine A1 receptor-mediated synaptic depression occurring at a presynaptic locus The adenosine A1 receptor-JNK signalling pathway may represent a novel mechanism underlying inhibition of neurotransmitter release in the CNS.