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α7 nicotinic acetylcholine receptor upregulation by anti-apoptotic Bcl-2 proteins

Author

Listed:
  • G. Brent Dawe

    (Janssen Pharmaceutical Companies of Johnson & Johnson)

  • Hong Yu

    (Janssen Pharmaceutical Companies of Johnson & Johnson)

  • Shenyan Gu

    (Janssen Pharmaceutical Companies of Johnson & Johnson)

  • Alissa N. Blackler

    (Janssen Pharmaceutical Companies of Johnson & Johnson)

  • Jose A. Matta

    (Janssen Pharmaceutical Companies of Johnson & Johnson)

  • Edward R. Siuda

    (Janssen Pharmaceutical Companies of Johnson & Johnson
    Alkermes, Inc.)

  • Elizabeth B. Rex

    (Janssen Pharmaceutical Companies of Johnson & Johnson
    Janssen Scientific Affairs, LLC)

  • David S. Bredt

    (Janssen Pharmaceutical Companies of Johnson & Johnson)

Abstract

Nicotinic acetylcholine receptors (nAChRs) mediate and modulate synaptic transmission throughout the brain, and contribute to learning, memory, and behavior. Dysregulation of α7-type nAChRs in neuropsychiatric as well as immunological and oncological diseases makes them attractive targets for pharmaceutical development. Recently, we identified NACHO as an essential chaperone for α7 nAChRs. Leveraging the robust recombinant expression of α7 nAChRs with NACHO, we utilized genome-wide cDNA library screening and discovered that several anti-apoptotic Bcl-2 family proteins further upregulate receptor assembly and cell surface expression. These effects are mediated by an intracellular motif on α7 that resembles the BH3 binding domain of pro-apoptotic Bcl-2 proteins, and can be blocked by BH3 mimetic Bcl-2 inhibitors. Overexpression of Bcl-2 member Mcl-1 in neurons enhanced surface expression of endogenous α7 nAChRs, while a combination of chemotherapeutic Bcl2-inhibitors suppressed neuronal α7 receptor assembly. These results demonstrate that Bcl-2 proteins link α7 nAChR assembly to cell survival pathways.

Suggested Citation

  • G. Brent Dawe & Hong Yu & Shenyan Gu & Alissa N. Blackler & Jose A. Matta & Edward R. Siuda & Elizabeth B. Rex & David S. Bredt, 2019. "α7 nicotinic acetylcholine receptor upregulation by anti-apoptotic Bcl-2 proteins," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10723-x
    DOI: 10.1038/s41467-019-10723-x
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