Unraveling the Molecular Reason of Opposing Effects of α‐Mangostin and Norfluoxetine on TREK‐2 at the Same Binding Site

Abstract

TWIK‐related K(+) channel (TREK)‐2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK‐2 is of significance for the development of new analgesics. Recent studies have shown that α‐Mangostin (α‐MG) activates TREK‐2, facilitating analgesic effects, yet the underlying molecular mechanisms remain elusive. Intriguingly, even though norfluoxetine (NFx) is known to inhibit TREK‐2, α‐MG is also observed to share the same binding site with NFx, and this implies that TREK‐2 might be modulated in a highly complicated manner. Therefore, we examine the mechanism of how TREK‐2 is activated by α‐MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how α‐MG and NFx exhibit opposing effects at the same binding site of TREK‐2. These findings will broaden our understanding of TREK‐2 modulation, providing clues for designing novel analgesic drugs.