Licorice metabolite 18β‐glycyrrhetinic acid activates G protein‐gated inwardly rectifying K+ channels

Background and Purpose Licorice (liquorice) is a common food additive and is used in Chinese medicine. Excess licorice intake can induce atrial fibrillation. Patients with atrial fibrillation possess constitutively activated G protein‐gated inwardly rectifying K+ (GIRK) channels. Whether licorice affects GIRK channel activity is unknown. We aimed to clarify the effects of licorice ingredients on GIRK current and the mechanism of action. Experimental Approach A major component of licorice, glycyrrhizic acid (GA), and its metabolite, 18β‐glycyrrhetinic acid (18β‐GA), were tested. We performed electrophysiological recordings in Xenopus oocytes to examine the effects of GA and 18β‐GA on various GIRK subunits (Kir3.1–Kir3.4), mutagenesis analyses to identify the crucial residues for drug action and motion analysis in cultured rat atrial myocytes to clarify effects of 18β‐GA on atrial functions. Key Results GA inhibited Kir3.1‐containing channels, while 18β‐GA activated all Kir3.x subunits. A pore helix residue Phe137 in Kir3.1 was critical for GA‐mediated inhibition, and the corresponding Ser148 in Kir3.2 was critical for 18β‐GA‐mediated activation. 18β‐GA activated GIRK channel in a Gβγ‐independent manner, whereas phosphatidylinositol 4,5‐bisphosphate (PIP2) was essential for activation. Glu236 located at the cytoplasmic pore of Kir3.2 appeared to be important to interactions with 18β‐GA. In rat atrial myocytes, 18β‐GA suppressed spontaneous beating via activation of GIRK channels. Conclusion and Implications GA acts as a novel GIRK inhibitor, and 18β‐GA acts as a novel GIRK activator. 18β‐GA alters atrial function via activation of GIRK channels. This study elucidates the pharmacological activity of licorice ingredients and provides information for drug design.