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

Abstract

Background and PurposeLicorice (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 ApproachA 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 ResultsGA 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 ImplicationsGA 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.

Glycyrrhetinic acid alleviates atrial fibrillation by inhibiting the expression of PIM1

“…Recently, some studies have initiated to explore the impact of GA upon cardiac arrhythmias. The study of Chen et al illustrated that GA might exert a therapeutic effect on AF by modulating ion channels in the heart, thereby affecting the electrical activity and reducing the irregular rhythm (Chen et al, 2023). However, these studies are still in the preliminary stages.…”

Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist

“…Given these important roles, inhibitors and activators of GIRKs have been broadly investigated. In addition to the G βγ subunit, GIRK channels were shown to be directly activated by Na + , PIP 2 , N-alcohols, Naringin, ML297, ivermectin (IVM), and 18-β glycyrrhetinic acid ( 4 , 5 , 6 , 7 , 8 , 9 , 10 ). Direct inhibitors were also identified including non-selective pore blockers such as Ba 2+ and Cs + , selective inhibitor tertiapin-Q, antipsychotic drugs such as thioridazine, clozapine, antidepressant drugs like imipramine and fluoxetine, and antihistamine like terfenadine ( 11 , 12 , 13 , 14 , 15 ).…”