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- methyfuronamide ≥ N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide >> N- methyl-1,3-di-n-butylxanthine-7-β-D-ribofuronamide ≥ 5'-N- ethylcarboxamidoadenosine ≥ 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, A(2A), and A(2B) receptors. In the presence of an A1/A2 antagonist, a selective A3 agonist only weakly inhibited forskolin- stimulated adenylyl cyclase activity in rat striatum. Thus, stimulation of phospholipase C 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.
|Titolo:||G protein-dependent activation of phospholipase C by adenosine A(3) receptors in rat brain|
ABBRACCHIO, MARIA PIA (Primo)
CATTABENI, FLAMINIO NICOLA (Ultimo)
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||1995|
|Appare nelle tipologie:||01 - Articolo su periodico|