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Modulation by sigma ligands of intracellular free Ca++ mobilization by N-methyl-D-aspartate in primary culture of rat frontal cortical neurons.
J Pharmacol Exp Ther. 1995 Oct; 275(1):207-14.JP

Abstract

Despite substantial data on radioligand binding to the sigma receptor, neither the physiologic function nor the intracellular mechanism of this receptor is known. In this study, we examined the effect of sigma ligands on Ca++ influx induced by N-methyl-D-aspartate (NMDA) in single primary cultured rat frontal cortical neurons with fluorescence video microscopy. All sigma ligands tested reduced the NMDA-induced increase in intracellular Ca++ concentration ([Ca++]i) in a dose-dependent manner with IC50 values in the low micromolar range. Inhibition by haloperidol and (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylam ine hydrochloride (JO1784) was noncompetitive; but, exogenous glycine (100 microM) did not alter their IC50 values. In addition, haloperidol (1 microM) enhanced Mg+(+)-mediated inhibition of the NMDA-induced [Ca++]i increase (IC50 = 0.45 +/- 0.01 mM vs. an IC50 = 0.98 +/- 0.06 mM for Mg++ alone). Selective sigma receptor ligands (JO1784, (+)-pentazocine) caused a greater reduction of the sustained phase of the Ca++ response to NMDA, whereas haloperidol and DTG reduced both the initial and sustained phase of the response to a similar degree. The rank order of potencies for inhibition of both the sustained Ca++ response phase and (+)-[3H]SKF-10047 binding (Roman et al., J. Pharm. Pharmacol. 42: 439-440, 1989) were similar. These findings suggest that sigma 1 ligands indirectly modulate NMDA receptor complex function through sigma 1 receptors and that sigma ligands facilitate the desensitization of the Ca++ response to NMDA.

Authors+Show Affiliations

Hayashi T
Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine, Japan.
Kagaya A
No affiliation info available
Takebayashi M
No affiliation info available
Shimizu M
No affiliation info available
Uchitomi Y
No affiliation info available
Motohashi N
No affiliation info available
Yamawaki S
No affiliation info available

MeSH

AnimalsBinding SitesBinding, CompetitiveCalciumCells, CulturedCerebral CortexDopamine D2 Receptor AntagonistsDrug InteractionsFemaleGlycineHaloperidolIntracellular FluidLigandsMagnesiumMicroscopy, FluorescenceN-MethylaspartateNeuronsPregnancyRatsRats, WistarReceptors, N-Methyl-D-AspartateReceptors, sigma

Pub Type(s)

Journal Article

Language

eng

PubMed ID

7562551

Citation

Hayashi, T, et al. "Modulation By Sigma Ligands of Intracellular Free Ca++ Mobilization By N-methyl-D-aspartate in Primary Culture of Rat Frontal Cortical Neurons." The Journal of Pharmacology and Experimental Therapeutics, vol. 275, no. 1, 1995, pp. 207-14.
Hayashi T, Kagaya A, Takebayashi M, et al. Modulation by sigma ligands of intracellular free Ca++ mobilization by N-methyl-D-aspartate in primary culture of rat frontal cortical neurons. J Pharmacol Exp Ther. 1995;275(1):207-14.
Hayashi, T., Kagaya, A., Takebayashi, M., Shimizu, M., Uchitomi, Y., Motohashi, N., & Yamawaki, S. (1995). Modulation by sigma ligands of intracellular free Ca++ mobilization by N-methyl-D-aspartate in primary culture of rat frontal cortical neurons. The Journal of Pharmacology and Experimental Therapeutics, 275(1), 207-14.
Hayashi T, et al. Modulation By Sigma Ligands of Intracellular Free Ca++ Mobilization By N-methyl-D-aspartate in Primary Culture of Rat Frontal Cortical Neurons. J Pharmacol Exp Ther. 1995;275(1):207-14. PubMed PMID: 7562551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation by sigma ligands of intracellular free Ca++ mobilization by N-methyl-D-aspartate in primary culture of rat frontal cortical neurons. AU - Hayashi,T, AU - Kagaya,A, AU - Takebayashi,M, AU - Shimizu,M, AU - Uchitomi,Y, AU - Motohashi,N, AU - Yamawaki,S, PY - 1995/10/1/pubmed PY - 1995/10/1/medline PY - 1995/10/1/entrez SP - 207 EP - 14 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 275 IS - 1 N2 - Despite substantial data on radioligand binding to the sigma receptor, neither the physiologic function nor the intracellular mechanism of this receptor is known. In this study, we examined the effect of sigma ligands on Ca++ influx induced by N-methyl-D-aspartate (NMDA) in single primary cultured rat frontal cortical neurons with fluorescence video microscopy. All sigma ligands tested reduced the NMDA-induced increase in intracellular Ca++ concentration ([Ca++]i) in a dose-dependent manner with IC50 values in the low micromolar range. Inhibition by haloperidol and (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylam ine hydrochloride (JO1784) was noncompetitive; but, exogenous glycine (100 microM) did not alter their IC50 values. In addition, haloperidol (1 microM) enhanced Mg+(+)-mediated inhibition of the NMDA-induced [Ca++]i increase (IC50 = 0.45 +/- 0.01 mM vs. an IC50 = 0.98 +/- 0.06 mM for Mg++ alone). Selective sigma receptor ligands (JO1784, (+)-pentazocine) caused a greater reduction of the sustained phase of the Ca++ response to NMDA, whereas haloperidol and DTG reduced both the initial and sustained phase of the response to a similar degree. The rank order of potencies for inhibition of both the sustained Ca++ response phase and (+)-[3H]SKF-10047 binding (Roman et al., J. Pharm. Pharmacol. 42: 439-440, 1989) were similar. These findings suggest that sigma 1 ligands indirectly modulate NMDA receptor complex function through sigma 1 receptors and that sigma ligands facilitate the desensitization of the Ca++ response to NMDA. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/7562551/Modulation_by_sigma_ligands_of_intracellular_free_Ca++_mobilization_by_N_methyl_D_aspartate_in_primary_culture_of_rat_frontal_cortical_neurons_ DB - PRIME DP - Unbound Medicine ER -