Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors

• Published in: International journal of molecular sciences Vol. 25; no. 6; p. 3390
• Main Authors: Marileo, Ana M, Lara, César O, Sazo, Anggelo, Contreras, Omayra V, González, Gabriel, Castro, Patricio A, Aguayo, Luis G, Moraga-Cid, Gustavo, Fuentealba, Jorge, Burgos, Carlos F, Yévenes, Gonzalo E
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.03.2024; MDPI
• Subjects: Alkaloids - chemistry; Analgesics; Animals; Binding sites; bioinformatics; electrophysiology; GABAA receptor; gamma-Aminobutyric Acid; Gelsemium - chemistry; Gelsemium alkaloids; glycine receptor; Indole Alkaloids - chemistry; Ligands; Mammals - metabolism; Plant Extracts - chemistry; Proteins; Rheumatoid arthritis; Spinal cord; Toxicity; glycine receptor; electrophysiology; GABAA receptor; Gelsemium alkaloids; bioinformatics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063390

Indole alkaloids are the main bioactive molecules of the genus plants. Diverse reports have shown the beneficial actions of alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA receptors (GABA Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.