%0 Journal Article %A Bertold J. Vilner %A Wayne D. Bowen %T Modulation of Cellular Calcium by Sigma-2 Receptors: Release from Intracellular Stores in Human SK-N-SH Neuroblastoma Cells %D 2000 %J Journal of Pharmacology and Experimental Therapeutics %P 900-911 %V 292 %N 3 %X 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. U.S. Government %U https://jpet.aspetjournals.org/content/jpet/292/3/900.full.pdf