Russian Journal of Biological Physics and Chemisrty Russian Journal of Biological Physics and Chemisrty АКТУАЛЬНЫЕ ВОПРОСЫ БИОЛОГИЧЕСКОЙ ФИЗИКИ И ХИМИИ 2499-9962 54831 10.29039/rusjbpc.2022.0494 МЕДИЦИНСКАЯ БИОФИЗИКА И БИОФИЗИЧЕСКАЯ ХИМИЯ MEDICAL BIOPHYSICS AND BIOPHYSICAL CHEMISTRY МЕДИЦИНСКАЯ БИОФИЗИКА И БИОФИЗИЧЕСКАЯ ХИМИЯ NEUROLEPTICS ATTENUATE Ca2+ RESPONSES INDUCED BY GLUTOXIM AND MOLIXAN IN MACROPHAGES Нейролептики подавляют Са2+-ответы, вызываемые глутоксимом и моликсаном в макрофагах Миленина Л. С. Milenina L. S. l.milenina@spbu.ru Крутецкая З. И. Krutetskaya Z. I. z.krutetskya@spbu.ru Антонов В. Г. Antonov V. G. Крутецкая Н. И. Krutetskaya N. I. Бадюлина В. И. Badulina V. I. Симонян А. О. Simonyan A. O. Санкт-Петербургский государственный университет Санкт-Петербург Россия Saint-Petersburg State University Saint Petersburg Russian Federation Санкт-Петербургский государственный университет Санкт-Петербург Россия Saint-Petersburg State University Saint Petersburg Russian Federation Санкт-Петербургский государственный педиатрический медицинский университет Санкт-Петербург Россия Saint-Petersburg State Pediatric Medical University Saint Petersburg Russian Federation Военно-Медицинская академия им. C.М. Кирова Санкт-Петербург Россия Kirov Military Medical Academy Saint Petersburg Russian Federation Санкт-Петербургский государственный университет Санкт-Петербург Россия Saint-Petersburg State University Saint Petersburg Russian Federation Санкт-Петербургский государственный университет Санкт-Петербург Россия Saint-Petersburg State University Saint Petersburg Russian Federation Санкт-Петербургский государственный университет Санкт-Петербург Россия Saint-Petersburg State University Saint Petersburg Russian Federation 25 03 2022 25 03 2022 7 1 127 136 20 03 2022 20 03 2022 https://rusjbpc.ru/en/nauka/article/54831/view

Галоперидол (производное бутирофенона) и производные фенотиазина хлорпромазин и трифлуоперазин относятся к первому поколению типичных нейролептиков и широко используются в клинической практике для терапии шизофрении и других психических заболеваний. Известно многогранное влияние этих нейролептиков на клеточные процессы. Так, выявлено высокое сродство типичных нейролептиков к рецепторам сигма-1. Рецепторы сигма-1 – повсеместные многофункциональные лигандрегулируемые молекулярные шапероны в мембране эндоплазматического ретикулума, имеющие уникальную историю, структуру и фармакологический профиль. Выполняя функции шаперонов, рецепторы сигма-1 модулируют широкий спектр клеточных процессов в норме и патологии, включая процессы Ca2+-сигнализации. Для выявления участия рецепторов сигма-1 в регуляции процессов Са2+-сигнализации в макрофагах, исследовали влияние лигандов рецепторов сигма-1 на Са2+-ответы, вызываемые дисульфидсодержащими иммуномодуляторами глутоксимом и моликсаном в перитонеальных макрофагах крысы. С использованием флуоресцентного Са2+-зонда Fura-2АМ показано, что галоперидол, хлорпромазин и трифлуоперазин значительно подавляют мобилизацию Са2+ из внутриклеточных Са2+-депо и последующий депозависимый вход Са2+ в клетку, индуцируемые глутоксимом и моликсаном в перитонеальных макрофагах. Полученные данные свидетельствуют о возможном участии рецепторов сигма-1 в комплексном сигнальном каскаде, вызываемом глутоксимом или моликсаном и приводящем к увеличению внутриклеточной концентрации Са2+ в макрофагах, а также об участии рецепторов сигма-1 в регуляции депозависимого входа Са2+ в макрофагах.

Haloperidol (butyrophenone derivative) and phenothiazine derivatives chlorpromazine and trifluoperazine belong to the typical first-generation neuroleptics and are widely used in clinical practice for treatment of schizophrenia and other mental diseases. Their multifaceted effect on cellular processes is well known. Thus, a high affinity of typical neuroleptics for sigma-1 receptors was revealed. Sigma-1 receptors are ubiquitous multifunctional ligand-operated molecular chaperones in the endoplasmic reticulum membrane with a unique history, structure, and pharmacological profile. Acting as chaperones, sigma-1 receptors modulate a wide range of cellular processes in health and disease, including Ca2+ signaling processes. To elucidate the involvement of sigma-1 receptors in Ca2+ signaling processes in macrophages, the effect of sigma-1 receptor ligands on Ca2+ responses induced by disulfide-containing immunomodulators glutoxim and molixan in rat peritoneal macrophages was investigated. Using Fura-2AM microfluorimetry we have shown that haloperidol, chlorpromazine and trifluoperazine significantly suppress both Ca2+ mobilization from intracellular Ca2+ stores and subsequent store-dependent Ca2+ entry, induced by glutoxim or molixan in peritoneal macrophages. The data obtained indicate the possible involvement of sigma-1 receptors in the complex signaling cascade triggered by glutoxim or molixan and leading to intracellular Ca2+ concentration increase in macrophages. The results also suggest the involvement of sigma-1 receptors in the regulation of store-dependent Ca2+ entry in macrophages.

 нейролептики рецепторы сигма-1 внутриклеточная концентрация Са2+ макрофаги neuroleptics sigma-1 receptors intracellular Ca2+ concentration macrophages Работа выполнена в рамках Договоров СПбГУ на выполнение научно-исследовательских работ № 01/18-НИОКР от 05.03.2018 и 05/03-20 от 12.03.2020.

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