{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:59:53Z","timestamp":1786121993152,"version":"build-2736575974"},"reference-count":74,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01-EY012347"],"award-info":[{"award-number":["R01-EY012347"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01-AG055357"],"award-info":[{"award-number":["R01-AG055357"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01-EY012347"],"award-info":[{"award-number":["R01-EY012347"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01-AG055357"],"award-info":[{"award-number":["R01-AG055357"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>N-methyl-D-aspartate (NMDA) receptors (NMDARs) are Ca2+-permeable ionotropic glutamate receptors in the brain that have critical roles in learning, memory, neural development, and synaptic plasticity. NMDARs are heterotetrameric Ca2+ channels, which open upon binding to the neurotransmitters, glutamate and glycine. Channel opening causes Ca2+ influx that activates a range of Ca2+-dependent cellular processes, including activation of Ca2+-dependent enzymes, which mediates various forms of synaptic plasticity. Prolonged channel opening elevates the intracellular Ca2+ level to a cytotoxic concentration. To maintain Ca2+ homeostasis, NMDAR channel activity is finely regulated by \u03b1-actinin (ACTN), which promotes channel opening by reducing the closed time, and by calmodulin (CaM), which promotes Ca2+-dependent channel desensitization (CDD). Defects in the regulation of NMDAR function are associated with a spectrum of neurological diseases. In this review, we integrate cryo-EM structures of NMDARs, NMR structures of the NMDAR cytosolic C0 domain of the GluN1 and GluN2A subunits bound to Ca2+-bound CaM (Ca2+-CaM), and various structures of \u03b1-actinin-1 (ACTN1) to construct structural models of NMDAR in the open channel state bound to Ca2+-free ACTN1 and the agonist-bound, desensitized channel state bound to Ca2+-CaM. These structural models provide insights into the Ca2+-dependent conformational changes that promote CDD.<\/jats:p>","DOI":"10.3390\/biom16081146","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T08:01:36Z","timestamp":1786089696000},"page":"1146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NMDA Receptor Regulation by Calmodulin and \u03b1-Actinin-1"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5561-1891","authenticated-orcid":false,"given":"Aritra","family":"Bej","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes W.","family":"Hell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0934-2595","authenticated-orcid":false,"given":"James B.","family":"Ames","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/361031a0","article-title":"A synaptic model of memory: Long-term potentiation in the hippocampus","volume":"361","author":"Bliss","year":"1993","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0143-4160(98)90061-6","article-title":"Ca2+ and synaptic plasticity","volume":"24","author":"Chittajallu","year":"1998","journal-title":"Cell Calcium"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nrn.2017.24","article-title":"NMDA receptors: Linking physiological output to biophysical operation","volume":"18","author":"Iacobucci","year":"2017","journal-title":"Nat. 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