Intracellular Crosstalk Between NMDA and Sigma-1 Receptors: A Novel Mechanistic Insight Relevant to Neuropsychiatric Pharmacotherapy
Katarzyna Lipke, Agnieszka Piwowar
Cells September 17, 2026 DOI: 10.3390/cells15181689 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
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| Key findings | The authors propose that the sigma-1 receptor and the NMDA receptor function as an integrated signaling axis, sharing pathways that regulate calcium homeostasis, kinase cascades, and gene transcription. They suggest that drugs such as ketamine, dextromethorphan, and memantine interact with both receptors, and that disruption of this crosstalk may contribute to excitatory imbalance in neuropsychiatric and neurodegenerative disorders. |
Abstract
Formerly recognized as an opioid receptor, the sigma-1 receptor (σ1R) is a multifunctional chaperone protein that plays a crucial role in regulating neuronal signaling, neuroprotection, and synaptic plasticity. Increasing evidence highlights a tight functional association between the σ1R and the N-methyl-D-aspartate receptor (NMDAR), a central mediator of excitatory neurotransmission and calcium-dependent neuronal processes. This review summarizes the shared signaling pathways underlying σ1R and NMDAR activity, including calcium homeostasis, calcium/calmodulin-dependent protein kinases (CaMKs), protein kinase C (PKC), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) cascades, as well as transcriptional regulators such as cAMP response element-binding protein (CREB), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and B-cell lymphoma 2 (Bcl-2). Experimental data demonstrate that pharmacological agents initially characterized as NMDAR antagonists—such as ketamine, dextromethorphan, and memantine—also interact with σ1R, suggesting that their therapeutic efficacy may arise from coordinated modulation of both receptor systems. These findings collectively indicate that the σ1R is a key regulatory element enabling proper NMDAR function and that disruption of this interaction may contribute to excitatory imbalance implicated in the pathophysiology of neuropsychiatric disorders. Recognizing the σ1R–NMDAR crosstalk as an integrated signaling axis may thus inform the development of dual-target therapeutic strategies aimed at improving neuronal resilience and clinical outcomes in psychiatric and neurodegenerative diseases.