The clinically used drug bupropion is used as an atypical antidepressant and smoking cessation drug that inhibits the reuptake of norepinephrine and dopamine. Subsequently it was shown that bupropion is also a non-competitive antagonist at nicotinic acetylcholine receptors (nAChRs) and serotonin type 3A and 3AB receptors (5-HT3ABRs), two eukaryotic cation-conducting pentameric ligand-gate ion channels (pLGICs). Recently, we identified and characterized a binding site for bupropion within the transmembrane domain of the procaryotic and cation-conducting pLGIC homologue from Gloeobacter violaceus , GLIC (Do et al. PMID:38678367). With the present study we interrogate whether bupropion also modulates anion-conducting pLGICs, specifically the type A γ-aminobutyric acid (GABA) receptor (GABA A R) that is targeted by drugs to treat epilepsy, anxiety, depression, and for anesthetics. The GABA A R family comprises at least 26 heterogeneous subtypes assembled from 19 different subunits. Each subtype is a pentameric channel that conducts chloride ions upon GABA binding to the β-α subunit interface. Previous studies of the GABA A R have identified binding sites for diverse compounds at different interfaces between specific subunits. Here, we determine the half maximal effective concentration (EC 50 ) of GABA and the half maximal inhibitory concentration (IC 50 ) of bupropion for three different subtypes of GABA A R, including synaptic and extrasynaptic subunit combinations. The subtypes were expressed in Xenopus laevis oocytes and electrophysiological recordings were obtained using a two-electrode voltage clamp setup. Future experiments will determine the exact binding site for bupropion within these channels.
Anderson et al. (Sun,) studied this question.