Modulation of cellular calcium by sigma-2 receptors: Release from intracellular stores in human SK-N-SH neuroblastoma cells

Human SK-N-SH neuroblastoma cells expressed sigma-1 and sigma-2 receptors w ith similar pharmacological profiles to those of rodent-derived tissues, al though sigma-2 receptors exhibited some affinity differences that might sug gest heterogeneity or species differences. Structurally diverse sigma ligan ds produced two types of increases in intracellular (cytosolic) Ca2+ concen tration ([Ca2+](i)) in these cells. CB-64D, CB-64L, JL-II-147, BD737, LR172 , BD1008, haloperidol, reduced haloperidol, and ibogaine all produced an im mediate, dose-dependent, and transient rise in [Ca2+](i). Sigma-inactive co mpounds structurally similar to the most active sigma ligands and ligands f or several neurotransmitter receptors produced little or no effect. The hig h activity of CB-64D and ibogaine (sigma-2-selective ligands) compared with the low activity of (+)-pentazocine and other (+)-benzomorphans (sigma-1-s elective ligands), in addition to enantioselectivity for CB-64D over CB-64L , strongly indicated mediation by sigma-2 receptors. The effect of CB-64D a nd BD737 was blocked by the sigma antagonists BD1047 and BD1063, further co nfirming specificity as a receptor-mediated event. The transient rise in [C a2+](i) occurred in the absence of extracellular Ca2+ and was completely el iminated by pretreatment of cells with thapsigargin. Thus, sigma-2 receptor s stimulate a transient release of Ca2+ from the endoplasmic reticulum. Pro longed exposure of cells to sigma-receptor ligands resulted in a latent and sustained rise in [Ca2+](i), with a pharmacological profile identical to t hat of the transient rise. This sustained rise in [Ca2+](i) was affected by neither the removal of extracellular Ca2+ nor thapsigargin pretreatment, s uggesting latent sigma-2 receptor-induced release from thapsigargin-insensi tive intracellular Ca2+ stores. Sigma-2 receptors may use Ca2+ signals in p roducing cellular effects.