IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-35025-7.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-35025-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-35025-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Maartje Westhoff & Silvia G. Villar & Taylor L. Voelker & Phung N. Thai & Heather C. Spooner & Alexandre D. Costa & Padmini Sirish & Nipavan Chiamvimonvat & Eamonn J. Dickson & Rose E. Dixon, 2024. "BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Declan Manning & L. Fernando Santana, 2022. "Regulating voltage-gated ion channels with nanobodies," Nature Communications, Nature, vol. 13(1), pages 1-2, December.
    3. Dingxi Zhou & Mariana Borsa & Daniel J. Puleston & Susanne Zellner & Jesusa Capera & Sharon Sanderson & Martina Schifferer & Svenja S. Hester & Xin Ge & Roman Fischer & Luke Jostins & Christian Behren, 2022. "Mapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35025-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.