Experimental and Computational Investigation of the Target and Mechanisms of Gelsemium Alkaloids in the Central Nervous System

<i>Gelsemium</i> has a long history of medicinal use but is also a poisonous plant. Some low-toxicity alkaloids in <i>Gelsemium</i> exhibit anxiolytic, anti-inflammatory, analgesic, and other pharmacological effects; however, certain alkaloids in <i>Gelsemium</i> are highly toxic. Nevertheless, the molecular targets underlying the biological effects of <i>Gelsemium</i> alkaloids remain poorly understood. We employed electrophysiological techniques and molecular modeling to examine the modulatory effects of <i>Gelsemium</i> alkaloids on inhibitory neurotransmitter receptors, as well as to elucidate the mechanisms underlying their molecular interactions. Our findings indicate that low-toxicity alkaloids primarily exert their pharmacological effects through actions on glycine receptors, with the binding site located at the orthosteric site between two α-subunits. Both highly toxic and low-toxicity alkaloids target GABAA receptors, using the β+/α- interface transmembrane structural domains as common binding sites. These results identify the targets through which <i>Gelsemium</i> alkaloids affect the central nervous system and predict the binding modes and key amino acids involved from a computational modeling perspective. However, further experimental validation through mutational studies is necessary to strengthen these findings.