G-protein-gated inwardly rectifying K + (GIRK) channel, composed of four subtypes (GIRK1-4), are expressed in various tissues including the brain and heart. GIRK channels are potential therapeutic targets for diseases such as alcohol addiction and atrial fibrillation. This study aimed to identify natural products that directly modulate GIRK channel activity and to elucidate their underlying modulatory mechanisms through comprehensive electrophysiological and mutagenesis analyses. (1) Glycyrrhizic acid (GA), a major ingredient of licorice ( Glycyrrhiza glabra ), inhibits GIRK currents, while its metabolite, 18β-glycyrrhetinic acid (18β-GA), activates them. Mutagenesis study revealed that a glutamate residue located at the cytoplasmic pore of GIRK is essential for 18β-GA-induced activation. (2) A steroid alkaloid derivative from Apocynaceae plants modulates GIRK activities in a subtype-specific manner: it activates cardiac-type GIRK channels but inhibits brain-type GIRK channels. A key tyrosine residue in the cytoplasmic region is required for this effect. Given that cardiac GIRK channels are constitutively activated in patients with chronic atrial fibrillation and that excess intake of licorice is linked to atrial fibrillation, we hypothesized that high concentrations of 18β-GA may affect atrial function by facilitating GIRK channel activity. Motion analyses using primary cultured rat atrial myocytes showed that 18β-GA suppress spontaneous beating, an effect reversed by the GIRK inhibitor tertiapin-Q. These findings suggest that 18β-GA downregulates atrial contraction via GIRK activation, potentially contributing to licorice-induced arrythmias. In conclusion, we identified novel GIRK modulators and clarified the structural determinants underlying their actions. These findings provide new insights into the novel gating mechanisms of GIRK channels and highlight physiological implications of GIRK channel regulation by natural products consumption.
Chen et al. (2026) studied this question.