ANGIOTENSIN-II RECEPTOR SUBTYPES ARE COUPLED WITH DISTINCT SIGNAL-TRANSDUCTION MECHANISMS IN NEURONS AND ASTROCYTES FROM RAT-BRAIN

Both neurons and astrocytes contain specific receptors for angiotensin II (AII). We used selective ligands for the AT1 and AT2 types of AII receptors to investigate the expression of functional receptor subtypes in astrocyte cultures and neuron cultures from 1-day-old (neonatal) rat brain. In astrocyte cultures, competition of I-125-labeled AII (I-125-AII) specific binding with AT1 (DuP753) or AT2 {PD123177, CGP42112A, [Phe(p-NH2)6]AII} selective receptor ligands revealed a potency series of AII > DuP753 > > > CGP42112A > [Phe(p-NH2)6]AII > PD123177. These results suggest a predominance of the AT, receptor subtype in neonatal astrocytes. Also, in astrocyte cultures, AII stimulated increases in inositolphospholipid hydrolysis that were significantly reduced by the AT1 receptor antagonist DuP753 but not altered by the AT2 receptor antagonist PD123177. In neonatal neuron cultures, competition of I-125-AII specific binding with the above ligands revealed a potency series of CGP42112A = AII > [Phe(p-NH2)6]AII > PD123177 >>> DuP753. I-125-AII specific binding to neonate neuronal cultures was reduced 73-84% by 1-mu-M PD123177, and the residual I-125-AII specific binding was eliminated by DuP753. Also, in neuron cultures, AII induced decreases in basal cGMP that were completely blocked by PD123177 or CGP42112A but not by DuP753. Our results suggest that astrocyte cultures from neonatal rat brains contain predominantly AT1 receptors that are coupled to a stimulation of inositolphospholipid hydrolysis. In contrast, neuron cultures from neonatal rat brain contain mostly AT2 receptors that are coupled to a reduction in basal cGMP levels, but a smaller Population of AT1 receptors is also present in these neurons.