Ottosson, N. E. | bioRxiv Science

bioRxiv2025

A broad set of synthetic cannabinoid receptor agonists inhibit the cardiac voltage-gated potassium channel hERG

Synthetic cannabinoid receptor agonists (SCRAs) is a large group of structurally diverse designer drugs (analogues of controlled substances) associated with intense and sometimes fatal intoxication. Cardiac symptoms including tachycardia and arrhythmia are common consequences of SCRA consumption. However, little is known about the mechanisms through which SCRAs may perturb cardiac rhythm. Here we used electrophysiological techniques to screen 36 SCRAs on two ion channels responsible for cardiomyocyte repolarization, hERG (also called KV11.1) and KV7.1/KCNE1. We report that the majority of tested SCRAs inhibited hERG, primarily by reducing channel conductance, and some also inhibited KV7.1/KCNE1. In silico data suggests that SCRAs use a known drug binding site in the pore of the hERG channel, shared by established hERG blockers like astemizole, where a planar SCRA molecule lays perpendicular to the ion conducting pathway. Experimental and in silico data identify SCRA structural features associated with prominent inhibitory effects on hERG, with chemical moieties allowing bond formation and/or the ability to fit into the vestibule being important. Structure-activity-relationships for SCRA effects on hERG, KV7.1/KCNE1 and the cannabinoid receptor 1 (CB1) varied, demonstrating the importance of assessing SCRA effects on multiple potential targets. In conclusion, we found SCRAs to be inhibitors of cardiac voltage-gated potassium channels important for cardiomyocyte repolarization. These results offer mechanistic insight into potentially detrimental SCRA effects on the heart and highlight the urgency of more extensive investigation of SCRAs on cardiac function.

pharmacology and toxicology↗

bioRxiv2020

Multiple binding sites for resin-acid derivatives on the voltage-sensor domain of the Shaker potassium channel

Voltage-gated potassium (KV) channels can be opened by negatively charged resin acids and their derivatives. These resin acids have been proposed to attract the positively charged voltage-sensor helix (S4) toward the extracellular side of the membrane by binding to a pocket located between the lipid-facing extracellular ends of the transmembrane segments S3 and S4. By contrast to this proposed mechanism, neutralization of the top gating charge of the Shaker KV channel increased resin-acid induced opening, suggesting other mechanisms and sites of action. Here we explored the binding of two resin-acid derivatives, Wu50 and Wu161, to the activated/open state of the Shaker KV channel by a combination of in-silico docking, molecular dynamics simulations, and electrophysiology of mutated channels. We identified three potential resin-acid binding sites around S4: (1) The S3/S4 site previously suggested, in which positively charged residues introduced at the top of S4 are critical to keep the compound bound, (2) a site in the cleft between S4 and the pore domain (S4/pore site), in which a tryptophan at the top of S6 and the top gating charge of S4 keeps the compound bound, and (3) a site located on the extracellular side of the voltage-sensor domain, in a cleft formed by S1-S4 (the top-VSD site). The multiple binding sites around S4 and the anticipated helical-screw motion of the helix during activation make the effect of resin-acid derivatives on channel function intricate. The propensity of a specific resin acid to activate and open a voltage-gated channel likely depends on its exact binding dynamics and the types of interactions it can form with the protein in a state-specific manner. eTOC SummarySilver[a] Ejneby et al use molecular dynamics simulations and electrophysiology to show that the voltage-gated Shaker potassium channel has multiple binding sites for resin-acid derivatives that can regulate its opening.

biophysics↗