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<p>Major depressive disorder (MDD) remains a critical global health burden, and a substantial proportion of patients exhibit insufficient responses to conventional monoaminergic antidepressants. Selective inhibition of the two-pore domain potassium channel TREK1 has emerged as a promising antidepressant strategy; however, the regulatory mechanisms controlling TREK1 trafficking—particularly its functional coupling with G protein–coupled receptors (GPCRs)—remain poorly understood. Here, we established a cell-based screening platform using a biomolecular luminescence complementation (BiLC) assay to monitor agonist-induced changes in membrane-associated TREK1. Using this platform, we identified a TREK1–5-hydroxytryptamine receptor 4 (HTR4) complex in vitro and in native hippocampal tissues using biomolecular fluorescence complementation (BiFC), co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA). Live-cell imaging demonstrated that treatment with the HTR4 agonist mosapride induces redistribution/internalization of a plasma membrane-associated TREK1–HTR4 pool into intracellular compartments. Electrophysiological recordings further confirmed that mosapride reduces TREK1 channel activity in an HTR4-dependent manner. In vivo, oral administration of mosapride for five days ameliorated lipopolysaccharide (LPS)-induced depressive-like behaviors in mice and preserved markers associated with hippocampal neurogenesis. Notably, viral expression of the TREK1 C-terminal interaction domain (C1), which competitively disrupts the TREK1–HTR4 complex, attenuated the neurogenic and behavioral effects of mosapride, supporting a causal role of TREK1 regulation in mediating these antidepressant-like actions. Collectively, our findings reveal a previously unrecognized mechanism in which HTR4 dynamically regulates TREK1 trafficking and function, and they highlight GPCR-based modulation of TREK1 as a potential therapeutic strategy for depressive disorders.</p>

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Mosapride promotes internalization of a TREK1–HTR4 complex and exerts rapid antidepressant-like effects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Soomin Lee,
  • Seung Chan Kim,
  • Junyeol Noh,
  • Gyunghwa Seo,
  • Yeonju Bae,
  • Sung Rae Kim,
  • Yaejin Yeon,
  • Seung Eun Lee,
  • Chang Man Ha,
  • Sunghoe Chang,
  • Jaekwang Lee,
  • Hoon Ryu,
  • Jae-Yong Park,
  • Eun Mi Hwang

摘要

Major depressive disorder (MDD) remains a critical global health burden, and a substantial proportion of patients exhibit insufficient responses to conventional monoaminergic antidepressants. Selective inhibition of the two-pore domain potassium channel TREK1 has emerged as a promising antidepressant strategy; however, the regulatory mechanisms controlling TREK1 trafficking—particularly its functional coupling with G protein–coupled receptors (GPCRs)—remain poorly understood. Here, we established a cell-based screening platform using a biomolecular luminescence complementation (BiLC) assay to monitor agonist-induced changes in membrane-associated TREK1. Using this platform, we identified a TREK1–5-hydroxytryptamine receptor 4 (HTR4) complex in vitro and in native hippocampal tissues using biomolecular fluorescence complementation (BiFC), co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA). Live-cell imaging demonstrated that treatment with the HTR4 agonist mosapride induces redistribution/internalization of a plasma membrane-associated TREK1–HTR4 pool into intracellular compartments. Electrophysiological recordings further confirmed that mosapride reduces TREK1 channel activity in an HTR4-dependent manner. In vivo, oral administration of mosapride for five days ameliorated lipopolysaccharide (LPS)-induced depressive-like behaviors in mice and preserved markers associated with hippocampal neurogenesis. Notably, viral expression of the TREK1 C-terminal interaction domain (C1), which competitively disrupts the TREK1–HTR4 complex, attenuated the neurogenic and behavioral effects of mosapride, supporting a causal role of TREK1 regulation in mediating these antidepressant-like actions. Collectively, our findings reveal a previously unrecognized mechanism in which HTR4 dynamically regulates TREK1 trafficking and function, and they highlight GPCR-based modulation of TREK1 as a potential therapeutic strategy for depressive disorders.