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Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.<\/jats:p>","DOI":"10.3390\/ijms232012196","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T22:21:11Z","timestamp":1665699671000},"page":"12196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling"],"prefix":"10.3390","volume":"23","author":[{"given":"Stephen M.","family":"Stahl","sequence":"first","affiliation":[{"name":"Department of Psychiatry, VAMC (SD), University of California, La Jolla, San Diego, CA 92093, USA"},{"name":"Neuroscience Education Institute, Carlsbad, CA 92008, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-8237","authenticated-orcid":false,"given":"Sara","family":"De Martin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2023-0749","authenticated-orcid":false,"given":"Andrea","family":"Mattarei","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35122 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"Bettini","sequence":"additional","affiliation":[{"name":"In Vitro Pharmacology Department, Aptuit, An Evotec Company, 37135 Verona, 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