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Structural mechanisms of assembly, gating, and calmodulin modulation of human olfactory CNG channel

Author

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  • Jing Xue

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Ninghai Gan

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Weizhong Zeng

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Youxing Jiang

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Mammalian cyclic nucleotide-gated (CNG) channels play crucial roles in visual and olfactory signal transduction. In olfactory sensory neurons, the native CNG channel functions as a heterotetramer consisting of CNGA2, CNGA4, and CNGB1b subunits and is activated by cAMP. Calmodulin (CaM) modulates the activity of the olfactory CNG channel, enabling rapid adaptation to odorants. Here we present cryo-EM structures of the native human olfactory CNGA2/A4/B1b channel in both CaM-bound closed and cAMP-bound open states, elucidating the molecular basis of the 2:1:1 subunit stoichiometry in channel assembly and the asymmetrical channel gating upon cAMP activation. Combining structural and functional analyses with AlphaFold prediction, we define two distinct CaM binding sites (CaM1 and CaM2) on the N- and C-terminal regions of CNGB1b, respectively, shedding light on the molecular mechanism of Ca2+/CaM-mediated rapid inhibition of the native olfactory CNG channel.

Suggested Citation

  • Jing Xue & Ninghai Gan & Weizhong Zeng & Youxing Jiang, 2025. "Structural mechanisms of assembly, gating, and calmodulin modulation of human olfactory CNG channel," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64436-5
    DOI: 10.1038/s41467-025-64436-5
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    References listed on IDEAS

    as
    1. Zhengshan Hu & Xiangdong Zheng & Jian Yang, 2023. "Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Noah G. Shuart & Yoni Haitin & Stacey S. Camp & Kevin D. Black & William N. Zagotta, 2011. "Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels," Nature Communications, Nature, vol. 2(1), pages 1-10, September.
    3. Takashi Kurahashi & Anna Menini, 1997. "Mechanism of odorant adaptation in the olfactory receptor cell," Nature, Nature, vol. 385(6618), pages 725-729, February.
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