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NEUROPHARMACOLOGY

Protein Kinase C-Dependent Potentiation of Intracellular Calcium Influx by ₁ Receptor Agonists in Rat Hippocampal Neurons

Hôpital Charcot, Plaisir, France (F.P.M.); Institut National de la Santé et de la Recherche Médicale Unité 488, Kremlin-Bicêtre, France (F.P.M., M.P.M.-S., J.L.); and Institut National de la Santé et de la Recherche Médicale Unité 442, Btiment 443, Campus d'Orsay, Université Paris Sud, Orsay, France (L.C.)

Intracellular calcium concentration ([Ca²⁺]_i) plays a major role in neuronal excitability, especially that triggered by the N-methyl-D-aspartate (NMDA)-sensitive glutamatergic receptor. We have previously shown that ₁ receptor agonists potentiate NMDA receptor-mediated neuronal activity in the hippocampus and recruit Ca²⁺-dependent second messenger cascades (e.g., protein kinase C; PKC) in brainstem motor structures. The present study therefore assessed whether the potentiating action of ₁ agonists on the NMDA response observed in the hippocampus involves the regulation of [Ca²⁺]_i and PKC. For this purpose, [Ca²⁺]_i changes after NMDA receptor activation were monitored in primary cultures of embryonic rat hippocampal pyramidal neurons using microspectrofluorometry of the Ca²⁺-sensitive indicator Fura-2/acetoxymethyl ester in the presence of ₁ agonists and PKC inhibitors. We show that successive activations of the ₁ receptor by 1-min pulses of (+)-benzomorphans or (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784) concommitantly with glutamate time dependently potentiated before inconstantly inhibiting the NMDA receptor-mediated increase of [Ca²⁺]_i, whereas 1,3-di-o-tolyl-guanidine, a mixed ₁/₂ agonist, did not significantly modify the glutamate response. Both potentiation and inhibition were prevented by the selective ₁ antagonist N,N-dipropyl-2-[4-methoxy-3-(211phenylethoxy) phenyl]-ethylamine monohydrochloride (NE-100). Furthermore, only (+)-benzomorphans could induce [Ca²⁺]_i influx by themselves after a brief pulse of glutamate. A pretreatment with the conventional PKC inhibitor 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole (Gö-6976) prevented the potentiating effect of (+)-benzomorphans on the glutamate response. Our results provide further support for a general mechanism for the intracellular ₁ receptor to regulate Ca²⁺-dependent signal transduction and protein phosphorylation.

Address correspondence to: Dr. F. P. Monnet, Institut National de la Santé et de la Recherche Médicale Unité 488, 80 rue du Général Leclerc, F-94276 Kremlin-Bicêtre cedex, France. E-mail: monnet{at}kb.inserm.fr

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