Amitriptyline is a tricyclic antidepressant widely used in clinical practice for the treatment of an-xiety and depression and chronic pain. These drugs have a multifaceted effect on cellular processes. One of their targets is sigma-1 receptors. Sigma-1 receptors are molecular chaperones located in the membrane of the endoplasmic reticulum; they are characterized by a unique structure and pharmacological profile. Sigma-1 receptors regulate many cellular processes in health and disease, including processes of Ca2+ signaling. Using Fura-2AM fluorescent Ca2+ probe, we showed for the first time that sigma-1 receptor agonist, the antidepressant amitriptyline, significantly suppresses Ca2+ mobilization from the intracellular Ca2+ stores and subsequent store-dependent Ca2+ entry into cells caused by inhibitors of endoplasmic Ca2+ ATPases thapsigargin and cyclopiazonic acid, as well as the disulfide-containing immunomodulators glutoxim and molixan, in rat peritoneal macrophages. The results indicate the participation of sigma-1 receptors in the complex signaling cascade caused by glutoxim or molixan, leading to an increase in intracellular Ca2+ concentration in macrophages. Data also indicate that sigma-1 receptors participate in the regulation of store-dependent Ca2+ entry in macrophages.

Amitriptyline is a tricyclic antidepressant widely used in clinical practice for the treatment of anxiety, depression and chronic pain. These drugs have a multifaceted effect on cellular processes. One of their targets is sigma-1 receptors. Sigma-1 receptors are molecular chaperones located in endoplasmic reticulum membrane; they are characterized by a unique structure and pharmacological profile. Sigma-1 receptors regulate many cellular processes in health and disease, including Ca2+ signaling. Using Fura-2AM microfluorimetry, it was shown for the first time that sigma-1 receptor agonist, antidepressant amitriptyline, significantly suppresses both Ca2+ mobilization from intracellular Ca2+-stores and subsequent store-dependent Ca2+ entry into cells, induced by endoplasmic Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid, as well as disulfide-containing immunomodulators glutoxim and molixan, in rat peritoneal macrophages. The results suggest the involvement of sigma-1 receptors in a complex signaling cascade induced by glutoxim or molixan, leading to an increase of intracellular Ca2+ concentration in macrophages. The results also indicate the participation of sigma-1 receptors in the regulation of store-dependent Ca2+ entry in macrophages.

Sigma-1 receptors are ubiquitous multifunctional ligand-regulated molecular chaperons in the membrane of the endoplasmic reticulum, having a unique history, structure and pharmacological profile. Sigma-1 receptors modulate a wide range of cellular processes in normal and pathological conditions, inclu-ding Ca2+ signaling processes. Using the Fura-2AM fluorescent Ca2+ probe, we have shown that sigma-1 receptor antagonist neuroleptic haloperidol significantly suppressed the mobilization of Ca2+ from intracellular Ca2+ stores and the subsequent store-dependent Ca2+ entry into cells caused by endoplasmic Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid, as well as immunomodulators glutoxim and molixan in rat peritoneal macrophages. The results indicated the participation of sigma-1 receptors in the complex signaling cascade caused by glutoxim or molixan and leading to an increase in intracellular Ca2+ concentration in macrophages, as well as the involvement of sigma-1 receptors in the regulation of store-dependent Ca2+ entry in macrophages.

The effect of the pharmacological analogue of oxidized glutathione, disulfide-containing immunomodulator molixan, on the Na+ transport in the frog skin epithelium was studied. Using the voltage-clamp method, it was shown for the first time that molixan modulated Na+ transport in the frog skin epithelium. It was found that the application of molixan from the apical surface of the skin suppressed Na+ transport, whereas when added from the basolateral surface, molixan mimicked the action of insulin and stimulated Na+ transport. The results indicate that oxidized glutathione and its pharmacological analogues molixan and glutoxim unidirectionally modulate Na+ transport in frog skin.

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.

— Store-dependent Ca 2+ entry is a ubiquitous mechanism of regulated Ca 2+ entry into eukaryotic cells. It is activated upon depletion of intracellular Ca 2+ stores and is involved in the regulation of a wide range of cellular processes. To elucidate the pharmacological characteristics of store-dependent Ca 2+ entry into cells, we studied the effect of YM-58483, pyrazole derivative immunosuppressant, on the store-dependent Ca 2+ entry in rat peritoneal macrophages induced by the endoplasmic Ca 2+ -ATPase inhibitors thapsigargin and cyclopiazonic acid, as well as the disulfide-containing immunomodulators glutoxim and molixan. Using Fura-2AM, fluorescent calcium indicator, it has been shown for the first time that, in rat peritoneal macrophages, as well as in other cell types, pyrazole derivative YM-58483 effectively inhibits store-dependent Ca 2+ entry and is a useful pharmacological tool to study the store-dependent Ca 2+ entry in macrophages. The data obtained additionally confirm that Ca 2+ entry induced by glutoxim or molixan is realized via the store-dependent mechanism.

С использованием флуоресцентного Са2+-зонда Fura-2AM впервые показано, что антагонист рецепторов сигма-1 - нейролептик хлорпромазин - значительно подавляет в перитонеальных макрофагах крыс депозависимый вход Са2+, индуцируемый иммуномодуляторами глутоксимом и моликсаном, а также ингибиторами эндоплазматических Са2+-АТФаз тапсигаргином и циклопьязониковой кислотой. Полученные результаты свидетельствуют об участии рецепторов сигма-1 в регуляции депозависимого входа Са2+ в макрофагах.

Using Fura-2AM microfluorimetry, we have shown for the first time that sigma-1 receptor antagonist neuroleptic chlorpromazine significantly inhibits glutoxim- and molixan-induced Ca 2+ responses and Ca 2+ responses induced by endoplasmic reticulum Са 2+ -ATPase inhibitors thapsigargin and cyclopiazonic acid in rat peritoneal macrophages. The results suggest the involvement of sigma-1 receptors in the signaling cascade induced by glutoxim or molixan and leading to intracellular Ca 2+ concentration increase and in the regulation of store-dependent Ca 2+ entry in macrophages.

Using the voltage-clamp technique, it has been shown for the first time that the neuroleptic drugs chlorpromazine and trifluoperazine, which act as sigma-1 receptor antagonists, attenuate Na+ transport in the frog skin epithelium. The results suggest that sigma-1 receptors may be involved in the regulation of transepithelial Na+ transport in frog skin.

Using Fura-2AM microfluorimetry we have shown for the first time that sigma-1 receptor agonist - tricyclic antidepressant amitriptyline - significantly inhibits store-dependent Ca2+ entry, induced by endoplasmic Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid, in rat peritoneal macrophages. The results suggest possible involvement of sigma-1 receptors in the regulation of store-dependent Ca2+ entry in macrophages.

Using voltage-clamp technique, the involvement of sigma-1 receptors in the regulation of Na+ transport in frog skin by the immunomodulatory drug glutoxim was investigated. We have shown for the first time that preincubation of the frog skin with the sigma-1 receptor antagonists haloperidol and chlorpromazine attenuates the stimulatory effect of glutoxim on the Na+ transport. The results suggest the possible involvement of the sigma-1 receptors in the regulation of Na+ transport in frog skin epithelium by glutoxim.

Using Fura-2AM microfluorimetry, we have shown for the first time that sigma-1 receptor agonist, tricyclic antidepressant amitriptyline, significantly inhibits glutoxim- and molixan-induced Ca2+-responses in rat peritoneal macrophages. The results suggest possible involvement of sigma-1 receptors in the signaling cascade induced by glutoxim or molixan and leading to intracellular Ca2+ concentration increase in macrophages.

The influence of the neuroleptic trifluoperazine on the intracellular concentration of Ca2+ in macrophages of rats was studied using a Fura-2AM fluorescent Ca2+ probe. It was found that trifluoperazine causes a dose-dependent increase in the intracellular Ca2+ concentration associated with Ca2+ mobilization from intracellular Ca2+ stores and subsequent entry of Ca2+ into peritoneal macrophages of rats. It was also shown that inhibitors of phospholipase A2 (4-bromophenacyl bromide, prednisolone, and dexamethasone), cyclooxygenases (aspirin and indomethacin), and lipoxygenases (caffeic acid, zileuton, and baicalein) suppress Ca2+ responses induced by trifluoperazine in macrophages. The data obtained indicate the participation of enzymes and/or products of the cascade of arachidonic acid metabolism in the influence of trifluoperazine on the intracellular concentration of Ca2+ in peritoneal macrophages.