Faculty of Medicine, University of Maribor, Maribor, Slovenia.
Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia.
PLoS Comput Biol. 2021 May 11;17(5):e1009002. doi: 10.1371/journal.pcbi.1009002. eCollection 2021 May.
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.
NMDA 受体促进胰腺β细胞复极化，从而减少葡萄糖刺激的胰岛素分泌。因此，NMDA 受体是治疗糖尿病的潜在靶点。虽然 NMDA 受体在β细胞中的抑制机制在分子水平上已经相当清楚，但到目前为止，尚未研究其对细胞集体活动的可能影响，尽管适当的胰岛素分泌模式是由β细胞行为的良好同步产生的。后者是通过强大的细胞间连接实现的，它控制着胰岛内钙波的传播，并使异质β细胞群体同步工作。由于细胞集体活动的中断是导致胰岛素分泌受损和葡萄糖耐量降低的一个重要且可能早期的因素，因此了解 NMDA 受体抑制对β细胞功能连接的可能影响至关重要。为了解决这个问题，我们将在小鼠组织切片中进行共聚焦功能多细胞钙成像与网络科学方法相结合。我们的结果表明，NMDA 受体抑制增加、同步和稳定β细胞活性，而不影响钙波的速度或大小。为了更精确地探索细胞间相互作用，我们利用多层网络形式化，将每个钙波视为一个单独的网络层，用加权有向连接描绘细胞间的传播。NMDA 受体抑制稳定了波发起者的作用和波的传播过程。用 NMDA 受体拮抗剂 MK-801 获得的发现，通过 dextrorphan（批准药物右美沙芬的活性代谢物）以及 NMDA 受体 KO 小鼠的实验得到了进一步验证。总之，我们的研究结果为 NMDA 受体抑制在治疗 2 型糖尿病中的可能作用提供了额外的新证据，并引入了多层网络范例作为一种通用策略，用于研究药物对多细胞系统连接的影响。
