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<p>G protein-coupled receptor (GPCR) dimers and higher-order oligomers are the subject of intense debates. The complexes formed between two or more different GPCRs enable the cell to integrate several signals. But the mechanisms of the allosteric interaction within these oligomers remain unclear. Here, we use as a model the heteromer formed in the brain between two targets of anti-psychotic drugs, the metabotropic glutamate receptor 2 (mGlu2) and the serotonin receptor 5-HT<sub>2A</sub>. Using molecular dynamics, a nanobody-based sensor and resonance energy transfer assays, we demonstrate that the 5-HT<sub>2A</sub> receptor behaves as a positive allosteric modulator by stabilizing the active conformation of mGlu2. Using cysteine cross-linking experiments and mGlu2 sensors, we reveal the molecular basis for this allosteric modulation of the mGlu2 receptor by 5-HT<sub>2A</sub>, an effect also mediated by other GPCRs. Our results thus provide insights into the allosteric control of a GPCR activity via heteromerization with another receptor.</p>

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Allosteric activation of the glutamate receptor mGlu2 by the serotonin receptor 5-HT2A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月27日

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  • Siyu Gai,
  • Li Lin,
  • Jiyong Meng,
  • Yichen Wu,
  • Li Xue,
  • Chanjuan Xu,
  • Qian Sun,
  • Adrià Ricarte,
  • James Dalton,
  • Pedro Renault,
  • Jesús Giraldo,
  • Jean-Philippe Pin,
  • Philippe Rondard,
  • Jianfeng Liu

摘要

G protein-coupled receptor (GPCR) dimers and higher-order oligomers are the subject of intense debates. The complexes formed between two or more different GPCRs enable the cell to integrate several signals. But the mechanisms of the allosteric interaction within these oligomers remain unclear. Here, we use as a model the heteromer formed in the brain between two targets of anti-psychotic drugs, the metabotropic glutamate receptor 2 (mGlu2) and the serotonin receptor 5-HT2A. Using molecular dynamics, a nanobody-based sensor and resonance energy transfer assays, we demonstrate that the 5-HT2A receptor behaves as a positive allosteric modulator by stabilizing the active conformation of mGlu2. Using cysteine cross-linking experiments and mGlu2 sensors, we reveal the molecular basis for this allosteric modulation of the mGlu2 receptor by 5-HT2A, an effect also mediated by other GPCRs. Our results thus provide insights into the allosteric control of a GPCR activity via heteromerization with another receptor.