G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain

MP Abbracchio, R Brambilla, S Ceruti, HO Kim, DK von Lubitz, KA Jacobson and F Cattabeni

Institute of Pharmacological Sciences, University of Milan, School of Pharmacy, Italy.

The recently cloned G protein-coupled adenosine A3 receptor has been proposed to play a role in the pathophysiology of cerebral ischemia. Because phospholipase C activation occurs as a very early response to brain ischemia, we evaluated the ability of A3- selective and nonselective adenosine analogues to elicit phosphoinositide hydrolysis. In myo-[3H]inositol-labeled rat striatal and hippocampal slices, A3 agonists stimulated formation of [3H]inositol phosphates in a concentration-dependent manner. In striatum, the potency order was 2- chloro-N6-(3-iodobenzyl)- adenosine-5'-N-methyluronamide > or = N6-(3- iodobenzyl)- adenosine-5'-N-methyluronamide >> N-methyl-1,3-di-n- butylxanthine-7-beta-D-ribofuronamide > or = 5'-N- ethylcarboxamidoadenosine > or = N6-2-(4-aminophenyl)-ethyladenosine > N6-(p-sulfophenyl)-adenosine = 1,3-dibutylxanthine-7- riboside, which is identical to the potency order in binding studies at cloned rat A3 receptors. Stimulation of phospholipase C activity was abolished by guanosine-5'-O-(2-thiodiphosphate), confirming the involvement of a G protein-coupled receptor. Activation of phospholipase C was higher in the striatum than in the hippocampus, consistent with A3 receptor densities. Stimulation of phospholipase C activity by adenosine analogues was only modestly antagonized by xanthine derivatives and at much higher concentrations than needed for blocking adenosine A1, A2A, and A2b receptors. In the presence of an A1/A2 antagonist, a selective A3 in rat striation. Thus, stimulation of phospholipase C activity agonist only weakly inhibited forskolin-stimulated adenylyl cyclase activity represents a principal transduction mechanism for A3 receptors in mammalian brain, and perhaps A3 receptor-mediated increases of inositol phosphates in the ischemic brain contribute to neurodegeneration by raising intracellular calcium levels.

Volume 48, Issue 6, pp. 1038-1045, 12/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

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