State-dependent inhibition of BK channels by the opioid agonist loperamide

Abstract

Large-conductance Ca2+-activated K+ (BK) channels control a range of physiological functions, and their dysfunction is linked to human disease. We have found that the widely used drug loperamide (LOP) can inhibit activity of BK channels composed of either α-subunits (BKα channels) or α-subunits plus the auxiliary γ1-subunit (BKα/γ1 channels), and here we analyze the molecular mechanism of LOP action. LOP applied at the cytosolic side of the membrane rapidly and reversibly inhibited BK current, an effect that appeared as a decay in voltage-activated BK currents. The apparent affinity for LOP decreased with hyperpolarization in a manner consistent with LOP behaving as an inhibitor of open, activated channels. Increasing LOP concentration reduced the half-maximal activation voltage, consistent with relative stabilization of the LOP-inhibited open state. Single-channel recordings revealed that LOP did not reduce unitary BK channel current, but instead decreased BK channel open probability and mean open times. LOP elicited use-dependent inhibition, in which trains of brief depolarizing steps lead to accumulated reduction of BK current, whereas single brief depolarizing steps do not. The principal effects of LOP on BK channel gating are described by a mechanism in which LOP acts as a state-dependent pore blocker. Our results suggest that therapeutic doses of LOP may act in part by inhibiting K+ efflux through intestinal BK channels.

The effects of loperamide on excitatory and inhibitory neuromuscular function in the human colon

“…It has been previously reported that the antimotility effects of loperamide are inhibited by naloxone. 24,42 Since naloxone is non-selective and also acts at 𝛿 and κ receptors, a likely explanation Several in vitro [44][45][46] and ex vivo 47,48 human studies have suggested that the anti-diarrheal effect of loperamide may be mediated by naloxone-insensitive, non-opioid receptor pathways. The proposed mechanisms of action include antagonism of voltage-gated sodium or calcium channels and/or calmodulin inhibition, which primarily alter ion transport and secretory function rather than neuromuscular function.…”

“…Several in vitro 44–46 and ex vivo 47,48 human studies have suggested that the anti‐diarrheal effect of loperamide may be mediated by naloxone‐insensitive, non‐opioid receptor pathways. The proposed mechanisms of action include antagonism of voltage‐gated sodium or calcium channels and/or calmodulin inhibition, which primarily alter ion transport and secretory function rather than neuromuscular function.…”