Sigma-1 Receptor Ligands Chlorpromazine and Trifluoperazine Attenuate Ca²⁺ 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 Ca²⁺ signaling. To elucidate the involvement of sigma-1 receptors in the processes of Ca²⁺ signaling in macrophages we studied the effect of sigma-1 receptor ligands, phenothiazine neuroleptics chlorpromazine and trifluoperazine, on Ca²⁺ responses induced by inhibitors of endoplasmic Ca²⁺-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 Ca²⁺ 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 Ca²⁺ concentration in macrophages. The results also indicate the involvement of sigma-1 receptors in the regulation of store-dependent Ca²⁺entry in macrophages.