Sigma-1 Receptor Ligands Chlorpromazine and Trifluoperazine Attenuate Ca Responses in Rat Peritoneal Macrophages.

Sigma-1 receptors are ubiquitous multifunctional ligand-regulated molecular chaperones in the endoplasmic reticulum membrane with a unique history, structure, and pharmacological profile. Sigma-1 receptors bind ligands of different chemical structure and pharmacological action and modulate a wide range of cellular processes in health and disease, including Ca signaling. To elucidate the involvement of sigma-1 receptors in the processes of Ca signaling in macrophages we studied the effect of sigma-1 receptor ligands, phenothiazine neuroleptics chlorpromazine and trifluoperazine, on Ca responses induced by inhibitors of endoplasmic Ca-ATPases thapsigargin and cyclopiazonic acid, as well as by disulfide-containing immunomodulators Glutoxim and Molixan in rat peritoneal macrophages. Using Fura-2AM microfluorimetry we showed for the first time that chlorpromazine and trifluoperazine inhibit both phases of Ca responses induced by Glutoxim, Molixan, thapsigargin, and cyclopiazonic acid in rat peritoneal macrophages. The data obtained indicate the participation of sigma-1 receptors in a complex signaling cascade caused by Glutoxim or Molixan and leading to an increase in intracellular Ca concentration in macrophages. The results also indicate the involvement of sigma-1 receptors in the regulation of store-dependent Caentry in macrophages.