{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:05:17Z","timestamp":1789646717322,"version":"4.0.0"},"reference-count":123,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009687","name":"Wroclaw Medical University","doi-asserted-by":"publisher","award":["SUBK.D150.26.008"],"award-info":[{"award-number":["SUBK.D150.26.008"]}],"id":[{"id":"10.13039\/501100009687","id-type":"DOI","asserted-by":"publisher"}]},{"award":["SUBK.D150.26.008"],"award-info":[{"award-number":["SUBK.D150.26.008"]}],"id":[{"id":"https:\/\/ror.org\/01qpw1b93","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Formerly recognized as an opioid receptor, the sigma-1 receptor (\u03c31R) 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 \u03c31R 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 \u03c31R 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-\u03baB), and B-cell lymphoma 2 (Bcl-2). Experimental data demonstrate that pharmacological agents initially characterized as NMDAR antagonists\u2014such as ketamine, dextromethorphan, and memantine\u2014also interact with \u03c31R, suggesting that their therapeutic efficacy may arise from coordinated modulation of both receptor systems. These findings collectively indicate that the \u03c31R 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 \u03c31R\u2013NMDAR 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.<\/jats:p>","DOI":"10.3390\/cells15181689","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:41:35Z","timestamp":1789645295000},"page":"1689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intracellular Crosstalk Between NMDA and Sigma-1 Receptors: A Novel Mechanistic Insight Relevant to Neuropsychiatric Pharmacotherapy"],"prefix":"10.3390","volume":"15","author":[{"given":"Katarzyna","family":"Lipke","sequence":"first","affiliation":[{"name":"Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-367 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Piwowar","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-367 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0193-953X(23)00042-4","article-title":"The Individual and Societal Burden of Treatment-Resistant Depression","volume":"46","author":"Jha","year":"2023","journal-title":"Psychiatr. 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