Intracellular Crosstalk Between NMDA and Sigma-1 Receptors: A Novel Mechanistic Insight Relevant to Neuropsychiatric Pharmacotherapy.

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.