Allosteric Site Mediates Inhibition of Tonic NMDA Receptor Activity by Low Dose Ketamine.

Autor:	Popescu G; Jacobs School of Medicine and Biomedical Sciences/University at Buffalo, SUNY., Abbott J; Jacobs School of Medicine and Biomedical Sciences/University at Buffalo, SUN., Wen H, Liu B; SUNY Buffalo., Gupta S; Jacobs School of Medicine and Biomedical Sciences/University at Buffalo, SUN., Iacobucci G; University at Buffalo., Zheng W
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Sep 21. Date of Electronic Publication: 2023 Sep 21.
DOI:	10.21203/rs.3.rs-3304783/v1
Abstrakt:	Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. At anesthetic doses, ketamine causes a drastic reduction in excitatory transmission by lodging in the centrally located hydrophilic pore of the NMDA receptor, where it blocks ionic flow. In contrast, the molecular and cellular targets responsible for the antidepressant effects of ketamine remain controversial. Here, we report functional and structural evidence that, at nanomolar concentrations, ketamine interacts with membrane-accessible hydrophobic sites where it stabilizes desensitized receptors to cause an incomplete, voltage- and pH-dependent reduction in NMDA receptor activity. This allosteric mechanism spares brief receptor activations and reduces preferentially currents from tonically active receptors. The hydrophobic site is a promising target for safe and effective therapies against acute and chronic neurodegeneration. Competing Interests: Declarations Competing interests: None
Databáze:	MEDLINE
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