The effects of sigma ligands and of neuropeptide Y on N‐methyl‐d‐aspartate‐induced neuronal activation of CA3 dorsal hippocampus neurones are differentially affected by pertussin toxin
Abstract:1 The in vivo effects of the high affinity sigma ligands 1,3-di(2-tolyl)guanidine (DTG), ( + )-Ncyclopropylmethyl-N-methyl-1,4-diphenyl-l-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784)
“…The fact that JO-1784 is inactive by itself on [Ca 2ϩ ] i (after a pulse of Glu) may support the notion that 1 receptors exhibit differential sensitivity to 1 agonists (Monnet et al, 1994) and suggests that the molecular mechanism by which (ϩ)-benzomorphans and JO-1784 reduce the glutamate response differs from that responsible for the enhancement of the Glu. Hayashi et al (1995) using primary neuronal culture have shown a similar inhibitory effect of DTG on the NMDA receptor-induced [Ca 2ϩ ] i influx that we did.…”
Intracellular calcium concentration ([Ca 2ϩ ] 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 Ca 2ϩ -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 [Ca 2ϩ ] i and PKC. For this purpose, [Ca 2ϩ ] i changes after NMDA receptor activation were monitored in primary cultures of embryonic rat hippocampal pyramidal neurons using microspectrofluorometry of the Ca 2ϩ -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 (ϩ)-benzomorphans or (ϩ)-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 [Ca 2ϩ ] 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-(211phe-nylethoxy) phenyl]-ethylamine monohydrochloride (NE-100). Furthermore, only (ϩ)-benzomorphans could induce [Ca 2ϩ ] 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 (ϩ)-benzomorphans on the glutamate response. Our results provide further support for a general mechanism for the intracellular 1 receptor to regulate Ca 2ϩ -dependent signal transduction and protein phosphorylation.
“…The fact that JO-1784 is inactive by itself on [Ca 2ϩ ] i (after a pulse of Glu) may support the notion that 1 receptors exhibit differential sensitivity to 1 agonists (Monnet et al, 1994) and suggests that the molecular mechanism by which (ϩ)-benzomorphans and JO-1784 reduce the glutamate response differs from that responsible for the enhancement of the Glu. Hayashi et al (1995) using primary neuronal culture have shown a similar inhibitory effect of DTG on the NMDA receptor-induced [Ca 2ϩ ] i influx that we did.…”
Intracellular calcium concentration ([Ca 2ϩ ] 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 Ca 2ϩ -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 [Ca 2ϩ ] i and PKC. For this purpose, [Ca 2ϩ ] i changes after NMDA receptor activation were monitored in primary cultures of embryonic rat hippocampal pyramidal neurons using microspectrofluorometry of the Ca 2ϩ -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 (ϩ)-benzomorphans or (ϩ)-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 [Ca 2ϩ ] 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-(211phe-nylethoxy) phenyl]-ethylamine monohydrochloride (NE-100). Furthermore, only (ϩ)-benzomorphans could induce [Ca 2ϩ ] 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 (ϩ)-benzomorphans on the glutamate response. Our results provide further support for a general mechanism for the intracellular 1 receptor to regulate Ca 2ϩ -dependent signal transduction and protein phosphorylation.
“…Implication of pertussis toxin-sensitive heterotrimeric G i͞o proteins has been proposed previously in the immediate in vivo and in vitro modulation by 1 ligands of neuronal firing and potassium conductance (8)(9)(10). Here, we bring further support to this notion as we show that the intracellular steps of 1 receptor activation result in the recruitment of the subsequent, calcium-dependent PLC͞PKC cascade.…”
Section: Discussionmentioning
confidence: 93%
“…These characteristics, although alleviating the controversy on the 1 receptor molecular reality, do not fit with its currently proposed mechanisms of action on potassium conductances and coupling with heterotrimeric membrane-bound G proteins (8)(9)(10).…”
Most physiological effects of 1 receptor ligands are sensitive to pertussis toxin, suggesting a coupling with cell membrane-bound G proteins. However, the cloning of the 1 receptor has allowed the identification of an intracellular protein anchored on the endoplasmic reticulum. Here, we show, using the isolated adult guinea pig brainstem preparation, that activation of the 1 receptor results in its translocation from the cytosol to the vicinity of the cell membrane and induces a robust and rapid decrease in hypoglossal activity, which is mediated by phospholipase C. The subsequent activation of protein kinase C  1 and  2 isoforms and the phosphorylation of a protein of the same molecular weight as the cloned 1 receptor lead to a desensitization of the 1 motor response. Our results indicate that the intracellular 1 receptor regulates several components implicated in plasma membrane-bound signal transduction. This might be an example of a mechanism by which an intracellular receptor modulates metabotropic responses.
“…Interestingly, in particular conditions, e.g. following Gi/o protein inactivation by pertussis toxin, haloperidol fails to reverse the effect of a agonists on the NMDA-induced neuronal activation (Monnet et al, 1994).…”
1It is now widely accepted that there are two classes of sigma (a) binding sites, denoted and°2, and recently 3 subtype has been proposed. Selective c, and c2 receptor agonists are known to modulate the neuronal response to N-methyl-D-aspartate (NMDA) Conversely, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) blocked the effects of (+)-pentazocine as well as those of BD-737, but not those of DTG. 5 The present results provide in vitro functional evidence for a a receptor type preferentially sensitive to BD-737, reduced haloperidol, BD-1008 and also to NE-100, that differs from the already identified ci, ci2 and ci3 sites.
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