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<p>Transient receptor potential (TRP) ion channels form heteromers through combinatorial associations of distinct subunits, contributing to the diversity of TRP channel functions. Among them, TRPC5, which forms a heteromer with TRPC1, represents an attractive pharmaceutical target for treating anxiety and depression. Here, we present the cryo-electron microscopy structure of the human TRPC1/C5 heteromer, composed of one TRPC1 subunit and three TRPC5 subunits. The incorporation of TRPC1 into the heteromer disrupts the C<sub>4</sub> symmetry of the TRPC5 homotetramer, resulting in a distinct ion conduction pathway characterized by an asymmetrically constricted selectivity filter and an asymmetric lower gate. The TRPC1/C5 heteromer displays recognizable structural features compared to the TRPC1/C4 heteromer, including a noncanonically tilted coiled-coil domain and a distinct intersubunit interactions. Furthermore, we elucidate the structures of human TRPC5 bound to the TRPC1/4/5-specific agonist, (−)-Englerin A. Our findings establish a foundation for exploring the diversity of heteromeric TRP channels and pave the way for targeting TRPC1/C5 as a therapeutic strategy.</p>

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Molecular architecture of the human TRPC1/C5 heteromeric channel

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Sun-Hong Kim,
  • Hyunwoo Park,
  • Jinhyeong Kim,
  • Hana Kang,
  • Jongdae Won,
  • Byoung-Cheol Lee,
  • Insuk So,
  • Hyung Ho Lee

摘要

Transient receptor potential (TRP) ion channels form heteromers through combinatorial associations of distinct subunits, contributing to the diversity of TRP channel functions. Among them, TRPC5, which forms a heteromer with TRPC1, represents an attractive pharmaceutical target for treating anxiety and depression. Here, we present the cryo-electron microscopy structure of the human TRPC1/C5 heteromer, composed of one TRPC1 subunit and three TRPC5 subunits. The incorporation of TRPC1 into the heteromer disrupts the C4 symmetry of the TRPC5 homotetramer, resulting in a distinct ion conduction pathway characterized by an asymmetrically constricted selectivity filter and an asymmetric lower gate. The TRPC1/C5 heteromer displays recognizable structural features compared to the TRPC1/C4 heteromer, including a noncanonically tilted coiled-coil domain and a distinct intersubunit interactions. Furthermore, we elucidate the structures of human TRPC5 bound to the TRPC1/4/5-specific agonist, (−)-Englerin A. Our findings establish a foundation for exploring the diversity of heteromeric TRP channels and pave the way for targeting TRPC1/C5 as a therapeutic strategy.