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In neurons, these channels are activated through a coordinated response to both signals; however, for BK channels to respond to physiological voltage changes, elevated concentrations of intracellular Ca2+ (ranging from 1 to 10 \u03bcM) are necessary. In many physiological contexts, BK channels are typically localized within nanodomains near Ca2+ sources (\u223c20\u201350 nm), such as N-methyl-D-aspartate receptors (NMDARs; encoded by the GRIN genes). Since the direct evidence of NMDAR\u2013BK channel coupling reported by Isaacson and Murphy in 2001 in the olfactory bulb, further studies have identified functional coupling between NMDARs and BK channels in other regions of the brain, emphasizing their importance in neuronal function. Mutations in the genes encoding NMDAR subunits have been directly linked to developmental encephalopathies, including intellectual disability, epilepsy, and autism spectrum features. Specifically, mutations V15M and V618G in the GRIN2B gene, which encodes the GluN2B subunit of NMDARs, are implicated in the pathogenesis of GRIN2B-related neurodevelopmental disorders. Here, we explored the effects of these two GluN2B mutations on NMDAR\u2013BK channel coupling, employing a combination of electrophysiological, biochemical, and imaging techniques. Taken together, our results demonstrate that mutation V618G specifically disrupts NMDAR\u2013BK complex formation, impairing functional coupling, in spite of robust individual channel expression in the membrane. These results provide a potential mechanistic basis for GRIN2B-related pathophysiology and uncover new clues about NMDAR\u2013BK complex formation.<\/jats:p>","DOI":"10.1085\/jgp.202513799","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T02:20:29Z","timestamp":1751941229000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["GRIN2B disease-associated mutations disrupt the function of BK channels and NMDA receptor signaling nanodomains"],"prefix":"10.1085","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8982-2494","authenticated-orcid":true,"given":"Rebeca","family":"Mart\u00ednez-L\u00e1zaro","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01r9z8p25","id-type":"ROR","asserted-by":"publisher"}],"name":"Universidad de La Laguna 1 Departamento de Ciencias M\u00e9dicas B\u00e1sicas-Fisiolog\u00eda, , 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