“The functions of the glycine receptor (GlyR) and γ-aminobutyric acid type A receptor (GABAAR) 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 GABAAR in hyperekplexia remains unknown.
Here, we show that dehydroxylcannabidiol (DH-CBD), a synthetic nonpsychoactive cannabinoid, restores both the GABA- and glycine-activated currents (IGABA and IGly ) in HEK-293 cells co-expressing a major GABAAR 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 GABAAR 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 IGABA and IGly currents. This S296A substitution also considerably attenuated the DH-CBD-induced disruption of the interaction between GlyRα1 R271Q and GABAAR.
These findings suggest that because it restores the functions of both GlyRα1 and GABAAR, 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