The functions of the glycine receptor (GlyR) and GABA_A receptor (GABA_AR) are both impaired in hyperekplexia, a neurological disorder usually caused by GlyR mutations. Although emerging evidence indicates that cannabinoids can directly restore normal GlyR function, whether they affect GABA_AR in hyperekplexia remains unknown. Here we show that dehydroxylcannabidiol (DH-CBD), a synthetic nonpsychoactive cannabinoid, restores the GABA- and glycine-activated currents (I_GABA and I_Gly , respectively) in HEK293 cells coexpressing a major GABA_AR isoform (α₁β₂γ₂) and GlyRα₁ carrying a human hyperekplexia-associated mutation (GlyRα₁^R271Q). Using coimmunoprecipitation and FRET assays, we found that DH-CBD disrupts the protein interaction between GABA_AR and GlyRα₁^R271Q Furthermore, a point mutation of GlyRα₁, changing Ser-296 to Ala-296, which is critical for cannabinoid binding on GlyR, significantly blocked DH-CBD-induced restoration of I_GABA and I_Gly currents. This S296A substitution also considerably attenuated DH-CBD-induced disruption of the interaction between GlyRα₁^R271Q and GABA_AR. These findings suggest that, because it restores the functions of both GlyRα₁ and GABA_AR, DH-CBD may represent a potentially valuable candidate drug to manage hyperekplexia.

#	Concept	H-Index	Publications	Citations
1	Medicine	5	5	200
2	Social Sciences	3	3	103
3	Health Sciences	2	2	97
4	Engineering	1	1	36
5	Biomedical Engineering	1	1	36

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