20.500.12556/DKUM-91113 NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity insights through multilayer network analysis NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cellular activity have not been addressed to date, even though proper insulin secretion patterns result from well-synchronized beta cell behavior. The latter is enabled by strong intercellular connectivity, which governs propagating calcium waves across the islets and makes the heterogeneous beta cell population work in synchrony. Since a disrupted collective activity is an important and possibly early contributor to impaired insulin secretion and glucose intolerance, it is of utmost importance to understand possible effects of NMDA receptor inhibition on beta cell functional connectivity. To address this issue, we combined confocal functional multicellular calcium imaging in mouse tissue slices with network science approaches. Our results revealed that NMDA receptor inhibition increases, synchronizes, and stabilizes beta cell activity without affecting the velocity or size of calcium waves. To explore intercellular interactions more precisely, we made use of the multilayer network formalism by regarding each calcium wave as an individual network layer, with weighted directed connections portraying the intercellular propagation. NMDA receptor inhibition stabilized both the role of wave initiators and the course of waves. The findings obtained with the experimental antagonist of NMDA receptors, MK-801, were additionally validated with dextrorphan, the active metabolite of the approved drug dextromethorphan, as well as with experiments on NMDA receptor KO mice. In sum, our results provide additional and new evidence for a possible role of NMDA receptor inhibition in treatment of type 2 diabetes and introduce the multilayer network paradigm as a general strategy to examine effects of drugs on connectivity in multicellular systems. pancreas beta cells insulin Islets of Langerhans trebušna slinavka beta celice inzulin Langerhansovi otočki true false true Public Library of Science Angleški jezik Slovenski jezik Znanstveno delo 2024-11-08 03:06:53 2024-11-29 12:22:10 2024-11-30 03:14:34 0000-00-00 00:00:00 2021 0 0 str. 1-29 št. 5 Letn. 17 Maj 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2020-11-06 2021-11-26 2021-05-11 612.349.7 63055107 10.1371/journal.pcbi.1009002 1553-734X RAZ_Sterk_Marko_2021.pdf RAZ_Sterk_Marko_2021.pdf 1 55F59448846EA2B0CCD868307024BAD1 5e9298ffc751eea2484674ff7123de38bc9d22aa7e3834ca08527d67cf0df9ab 17d4b2a0-ae48-11ef-8753-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=187024 https://doi.org/10.1371/journal.pcbi.1009002 0 3e987026-ae48-11ef-8753-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=187025 Medicinska fakulteta Fakulteta za naravoslovje in matematiko Pedagoška fakulteta 0 0 0