Non-sedating antihistamines block G-protein-gated inwardly rectifying K+ channels

Background and Purpose A second-generation antihistamine, terfenadine, is known to induce arrhythmia by blocking hERG channels. In this study, we have shown that terfenadine also inhibits the activity of G-protein-gated inwardly rectifying K+ (GIRK) channels, which regulate the excitability of neurons and cardiomyocytes. To clarify the underlying mechanism(s), we examined the effects of several antihistamines on GIRK channels and identified the structural determinant for the inhibition. Experimental Approach Electrophysiological recordings were made in Xenopus oocytes and rat atrial myocytes to analyse the effects of antihistamines on various GIRK subunits (K(ir)3.x). Mutagenesis analyses identified the residues critical for inhibition by terfenadine and the regulation of ion selectivity. The potential docking site of terfenadine was analysed by molecular docking. Key Results GIRK channels containing K(ir)3.1 subunits heterologously expressed in oocytes and native GIRK channels in atrial myocytes were inhibited by terfenadine and other non-sedating antihistamines. In K(ir)3.1 subunits, mutation of Phe137, located in the centre of the pore helix, to the corresponding Ser in K(ir)3.2 subunits reduced the inhibition by terfenadine. Introduction of an amino acid with a large side chain in K(ir)3.2 subunits at Ser148 increased the inhibition. When this residue was mutated to a non-polar amino acid, the channel became permeable to Na+. Phosphoinositide-mediated activity was also decreased by terfenadine. Conclusion and Implications The Phe137 residue in K(ir)3.1 subunits is critical for inhibition by terfenadine. This study provides novel insights into the regulation of GIRK channels by the pore helix and information for drug design.