Neureiter Elizabeth G, Erickson-Oberg M Quincy, Nigam Aparna, Johnson Jon W
Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
Front Pharmacol. 2025 Apr 30;16:1561956. doi: 10.3389/fphar.2025.1561956. eCollection 2025.
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels present at most excitatory synapses in the brain that play essential roles in cognitive functions including learning and memory consolidation. However, NMDAR dysregulation is implicated in many nervous system disorders. Diseases that involve pathological hyperactivity of NMDARs can be treated clinically through inhibition by channel blocking drugs. NMDAR channel block can occur via two known mechanisms. First, in traditional block, charged drug molecules can enter the channel directly from the extracellular solution after NMDAR activation and channel opening. Second, uncharged molecules of channel blocking drug can enter the hydrophobic plasma membrane, and upon NMDAR activation the membrane-associated drug can transit into the channel through a fenestration within the NMDAR. This membrane-associated mechanism of action is called membrane to channel inhibition (MCI) and is not well understood despite the clinical importance of NMDAR channel blocking drugs. Intriguingly, a hydrophobic route of access for drugs is not unique to NMDARs. Our review will address inhibition of NMDARs and other ion channels by membrane-associated drugs and consider how the path of access may affect a drug's therapeutic potential.
N-甲基-D-天冬氨酸受体（NMDARs）是存在于大脑中大多数兴奋性突触处的配体门控离子通道，在包括学习和记忆巩固在内的认知功能中发挥着重要作用。然而，NMDAR功能失调与许多神经系统疾病有关。涉及NMDARs病理性过度活跃的疾病可通过通道阻断药物进行临床治疗。NMDAR通道阻断可通过两种已知机制发生。首先，在传统阻断中，带电荷的药物分子可在NMDAR激活和通道开放后直接从细胞外溶液进入通道。其次，通道阻断药物的不带电荷分子可进入疏水的质膜，在NMDAR激活后，与膜相关的药物可通过NMDAR内的一个小孔转运到通道中。这种与膜相关的作用机制称为膜到通道抑制（MCI），尽管NMDAR通道阻断药物具有临床重要性，但人们对其了解并不充分。有趣的是，药物的疏水进入途径并非NMDARs所特有。我们的综述将探讨与膜相关的药物对NMDARs和其他离子通道的抑制作用，并考虑进入途径如何影响药物的治疗潜力。
