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Selective posttranslational inhibition of CaVβ1-associated voltage-dependent calcium channels with a functionalized nanobody

Author

Listed:
  • Travis J. Morgenstern

    (Columbia University Irving Medical Center)

  • Neha Nirwan

    (University of California)

  • Erick O. Hernández-Ochoa

    (University of Maryland School of Medicine)

  • Hugo Bibollet

    (University of Maryland School of Medicine)

  • Papiya Choudhury

    (Columbia University Irving Medical Center)

  • Yianni D. Laloudakis

    (Columbia University Irving Medical Center)

  • Manu Johny

    (Columbia University Irving Medical Center)

  • Roger A. Bannister

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Martin F. Schneider

    (University of Maryland School of Medicine)

  • Daniel L. Minor

    (University of California
    University of California
    University of California
    University of California)

  • Henry M. Colecraft

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

Abstract

Ca2+ influx through high-voltage-activated calcium channels (HVACCs) controls diverse cellular functions. A critical feature enabling a singular signal, Ca2+ influx, to mediate disparate functions is diversity of HVACC pore-forming α1 and auxiliary CaVβ1–CaVβ4 subunits. Selective CaVα1 blockers have enabled deciphering their unique physiological roles. By contrast, the capacity to post-translationally inhibit HVACCs based on CaVβ isoform is non-existent. Conventional gene knockout/shRNA approaches do not adequately address this deficit owing to subunit reshuffling and partially overlapping functions of CaVβ isoforms. Here, we identify a nanobody (nb.E8) that selectively binds CaVβ1 SH3 domain and inhibits CaVβ1-associated HVACCs by reducing channel surface density, decreasing open probability, and speeding inactivation. Functionalizing nb.E8 with Nedd4L HECT domain yielded Chisel-1 which eliminated current through CaVβ1-reconstituted CaV1/CaV2 and native CaV1.1 channels in skeletal muscle, strongly suppressed depolarization-evoked Ca2+ influx and excitation-transcription coupling in hippocampal neurons, but was inert against CaVβ2-associated CaV1.2 in cardiomyocytes. The results introduce an original method for probing distinctive functions of ion channel auxiliary subunit isoforms, reveal additional dimensions of CaVβ1 signaling in neurons, and describe a genetically-encoded HVACC inhibitor with unique properties.

Suggested Citation

  • Travis J. Morgenstern & Neha Nirwan & Erick O. Hernández-Ochoa & Hugo Bibollet & Papiya Choudhury & Yianni D. Laloudakis & Manu Johny & Roger A. Bannister & Martin F. Schneider & Daniel L. Minor & Hen, 2022. "Selective posttranslational inhibition of CaVβ1-associated voltage-dependent calcium channels with a functionalized nanobody," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35025-7
    DOI: 10.1038/s41467-022-35025-7
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    References listed on IDEAS

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    1. Karl Deisseroth & E. Kevin Heist & Richard W. Tsien, 1998. "Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons," Nature, Nature, vol. 392(6672), pages 198-202, March.
    2. Guoxia Liu & Arianne Papa & Alexander N. Katchman & Sergey I. Zakharov & Daniel Roybal & Jessica A. Hennessey & Jared Kushner & Lin Yang & Bi-Xing Chen & Alexander Kushnir & Katerina Dangas & Steven P, 2020. "Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics," Nature, Nature, vol. 577(7792), pages 695-700, January.
    3. Pascal Béguin & Kazuaki Nagashima & Tohru Gonoi & Tadao Shibasaki & Kazuo Takahashi & Yasushige Kashima & Nobuaki Ozaki & Käthi Geering & Toshihiko Iwanaga & Susumu Seino, 2001. "Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem," Nature, Nature, vol. 411(6838), pages 701-706, June.
    4. Yu-hang Chen & Ming-hui Li & Yun Zhang & Lin-ling He & Yoichi Yamada & Aileen Fitzmaurice & Yang Shen & Hailong Zhang & Liang Tong & Jian Yang, 2004. "Structural basis of the α1–β subunit interaction of voltage-gated Ca2+ channels," Nature, Nature, vol. 429(6992), pages 675-680, June.
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    Cited by:

    1. Declan Manning & L. Fernando Santana, 2022. "Regulating voltage-gated ion channels with nanobodies," Nature Communications, Nature, vol. 13(1), pages 1-2, December.

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