“The functions of the glycine receptor (GlyR) and γ-aminobutyric acid type A receptor (GABA_AR) are both impaired in hyperekplexia, a neurological disorder that is usually caused by GlyR mutations.

Although emerging evidence indicates that cannabinoids can directly restore normal GlyR function, whether they affect the GABA_AR in hyperekplexia remains unknown.

Here, we show that dehydroxylcannabidiol (DH-CBD), a synthetic nonpsychoactive cannabinoid, restores both the GABA- and glycine-activated currents (I_GABA and I_Gly ) in HEK-293 cells co-expressing a major GABA_AR isoform (α₁β₂γ₂) and GlyRα₁ carrying a human hyperekplexia-associated mutation (GlyRα₁ ^R271Q). Using co-immunoprecipitation 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 the DH-CBD-induced restoration of I_GABA and I_Gly currents. This S296A substitution also considerably attenuated the 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.”

https://www.ncbi.nlm.nih.gov/pubmed/31757808

http://www.jbc.org/content/early/2019/11/22/jbc.RA119.011221