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Research ArticleCELLULAR AND MOLECULAR

Modulation of Cellular Calcium by Sigma-2 Receptors: Release from Intracellular Stores in Human SK-N-SH Neuroblastoma Cells

Bertold J. Vilner and Wayne D. Bowen
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 900-911;
Bertold J. Vilner
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Wayne D. Bowen
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Abstract

Human SK-N-SH neuroblastoma cells expressed sigma-1 and sigma-2 receptors with similar pharmacological profiles to those of rodent-derived tissues, although sigma-2 receptors exhibited some affinity differences that might suggest heterogeneity or species differences. Structurally diverse sigma ligands produced two types of increases in intracellular (cytosolic) Ca2+ concentration ([Ca2+]i) in these cells. CB-64D, CB-64L, JL-II-147, BD737, LR172, BD1008, haloperidol, reduced haloperidol, and ibogaine all produced an immediate, dose-dependent, and transient rise in [Ca2+]i. Sigma-inactive compounds structurally similar to the most active sigma ligands and ligands for several neurotransmitter receptors produced little or no effect. The high activity of CB-64D and ibogaine (sigma-2-selective ligands) compared with the low activity of (+)-pentazocine and other (+)-benzomorphans (sigma-1-selective ligands), in addition to enantioselectivity for CB-64D over CB-64L, strongly indicated mediation by sigma-2 receptors. The effect of CB-64D and BD737 was blocked by the sigma antagonists BD1047 and BD1063, further confirming specificity as a receptor-mediated event. The transient rise in [Ca2+]i occurred in the absence of extracellular Ca2+ and was completely eliminated by pretreatment of cells with thapsigargin. Thus, sigma-2 receptors stimulate a transient release of Ca2+ from the endoplasmic reticulum. Prolonged exposure of cells to sigma-receptor ligands resulted in a latent and sustained rise in [Ca2+]i, with a pharmacological profile identical to that of the transient rise. This sustained rise in [Ca2+]i was affected by neither the removal of extracellular Ca2+ nor thapsigargin pretreatment, suggesting latent sigma-2 receptor-induced release from thapsigargin-insensitive intracellular Ca2+ stores. Sigma-2 receptors may use Ca2+ signals in producing cellular effects.

Footnotes

  • Send reprint requests to: Wayne D. Bowen, Ph.D., Chief, Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, NIDDK/National Institutes of Health, Bldg. 8, Room B1-23, 8 Center Dr. MSC 0815, Bethesda, MD 20892-0815. E-mail:bowenw{at}bdg8.niddk.nih.gov

  • Abbreviations:
    DTG
    1,3-di-o-tolylguanidine
    [Ca2+]i
    intracellular (cytosolic) Ca2+ concentration
    DMEM
    Dulbecco's modified Eagle's medium
    SERCA
    sarcoplasmic-endoplasmic reticulum Ca2+-ATPase
    DPBS
    Dulbecco's phosphate-buffered saline
    IP3
    inositol-1,4,5-trisphosphate
    Red HAL
    reduced haloperidol
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin
    NMDA
    N-methyl-d-aspartate
    • Received May 21, 1999.
    • Accepted November 23, 1999.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleCELLULAR AND MOLECULAR

Modulation of Cellular Calcium by Sigma-2 Receptors: Release from Intracellular Stores in Human SK-N-SH Neuroblastoma Cells

Bertold J. Vilner and Wayne D. Bowen
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 900-911;

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Research ArticleCELLULAR AND MOLECULAR

Modulation of Cellular Calcium by Sigma-2 Receptors: Release from Intracellular Stores in Human SK-N-SH Neuroblastoma Cells

Bertold J. Vilner and Wayne D. Bowen
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 900-911;
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