Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels

Cannabis sativa has a long history of medicinal use, dating back to ancient times. This plant produces cannabinoids, which are now known to interact with several human proteins, including Cys-loop receptors for glycine (GlyR) and gamma-aminobutyric acid (GABA_AR). As these channels are the primary mediators of inhibitory signals, they contribute to the diverse effects of cannabinoids on the nervous system. Evidence suggests that cannabinoid binding sites are located within the transmembrane domain, although their precise location has remained undetermined for over a decade. The process of identification of the binding site and the computational approaches employed are the main subjects of this Perspective, which includes an analysis of the most recently resolved cryo-EM structures of zebrafish GlyR bound to Δ⁹-tetrahydrocannabinol and the THC-GlyR complex obtained through molecular dynamics simulations. With this work, we aim to contribute to guiding future studies investigating the molecular basis of cannabinoid action on inhibitory channels.