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

초록

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 alpha-Mangostin (alpha-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, alpha-MG is also observed to share a 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 alpha-MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how alpha-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. TWIK-related K+ channel (TREK)-2 has been considered as a promising target for the development of new analgesics, and it was demonstrated that alpha-mangostin, a potent activator of TREK-2, shares a binding site with the well-known inhibitor of TREK-2, norfluoxetine. Here, we illustrate the molecular reason of the opposing effects of these two ligands at the same binding site. image

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