p38 Mitogen-Activated Protein Kinase Contributes to Adenosine A1Receptor-Mediated Synaptic Depression in Area CA1 of the Rat Hippocampus

• DOI: 10.1523/jneurosci.4052-06.2006
• Publication Date: 2006-11-29T22:55:24Z
• Authors: Tyson B. Brust; Francisco S. Caya...; Ning Zhou; Brian A. MacVicar
• Keywords: Rats, Sprague-Dawley; 0303 health sciences; 03 medical and health sciences; Receptor, Adenosine A1; Long-Term Synaptic Depression; Animals; In Vitro Techniques; Hippocampus; Synaptic Transmission; p38 Mitogen-Activated Protein Kinases; Rats

Adenosine is arguably the most potent and widespread presynaptic modulator in the CNS, yet adenosine receptor signal transduction pathways remain unresolved. Here, we demonstrate a novel mechanism in which adenosine A1receptor stimulation leads to p38 mitogen-activated protein kinase (MAPK) activation and contributes to the inhibition of synaptic transmission. Western blot analysis indicated that selective A1receptor activation [withN6-cyclopentyladenosine (CPA)] resulted in rapid increases in phosphorylated p38 (phospho-p38) MAPK immunoreactivity in membrane fractions, and decreases in phospho-p38 MAPK in cytosolic fractions. Immunoprecipitation with a phospho-p38 MAPK antibody revealed constitutive association of this phosphoprotein with adenosine A1receptors. Phospho-p38 MAPK activation by A1receptor stimulation induced translocation of PP2a (protein phosphatase 2a) to the membrane. We then examined the actions of p38 MAPK activation in A1receptor-mediated synaptic inhibition. Excitatory postsynaptic field potentials evoked in area CA1 of the rat hippocampus markedly decreased in response to adenosine (10 μm), the A1receptor agonist CPA (40 nm), or a 5 min exposure to hypoxia. These inhibitory responses were mediated by A1receptor activation because the selective antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (100 nm) prevented them. In agreement with the biochemical analysis, the selective p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] (25 μm) blocked the inhibitory actions of A1receptor activation, whereas both the inactive analog SB202474 [4-ethyl-2-(p-methoxyphenyl)-5-(4′-pyridyl)-1H-imidazole] (25 μm) and the ERK 1/2 (extracellular signal-regulated kinase 1/2) MAPK inhibitor PD98059 [2′-amino-3′-methoxyflavone] (50 μm) were ineffective. In contrast, the p38 MAPK inhibitors did not inhibit GABAB-mediated synaptic depression. These data suggest A1receptor-mediated p38 MAPK activation is a crucial step underlying the presynaptic inhibitory effect of adenosine on CA3–CA1 synaptic transmission.