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 (K_ir 3.1-K_ir 3.4), 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 K_ir 3.1-containing channels, while 18β-GA activated all K_ir 3.x subunits. A pore helix residue Phe137 in K_ir 3.1 was critical for GA-mediated inhibition, and the corresponding Ser148 in K_ir 3.2 was critical for 18β-GA-mediated activation. 18β-GA activated GIRK channel in a G_βγ -independent manner, whereas phosphatidylinositol 4,5-bisphosphate (PIP₂ ) was essential for activation. Glu236 located at the cytoplasmic pore of K_ir 3.2 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.