title: Modulation of cellular calcium by sigma-2 receptors: release from intracellular stores in human SK-N-SH neuroblastoma cells.
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) Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](i) occurred in the absence of extracellular Ca(2+) and was completely eliminated by pretreatment of cells with thapsigargin. Thus, sigma-2 receptors stimulate a transient release of Ca(2+) from the endoplasmic reticulum. Prolonged exposure of cells to sigma-receptor ligands resulted in a latent and sustained rise in [Ca(2+)](i), with a pharmacological profile identical to that of the transient rise. This sustained rise in [Ca(2+)](i) was affected by neither the removal of extracellular Ca(2+) nor thapsigargin pretreatment, suggesting latent sigma-2 receptor-induced release from thapsigargin-insensitive intracellular Ca(2+) stores. Sigma-2 receptors may use Ca(2+) signals in producing cellular effects.
authors.affiliation: Unit on Receptor Biochemistry, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Vilner
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D009020:Morphine / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D017480:Receptors, sigma / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D015544:Inositol 1,4,5-Trisphosphate; D009020:Morphine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor