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Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology

Author

Listed:
  • Madhurima Dhara

    (Janssen Pharmaceutical Companies of Johnson and Johnson)

  • Jose A. Matta

    (Janssen Pharmaceutical Companies of Johnson and Johnson)

  • Min Lei

    (Janssen Pharmaceutical Companies of Johnson and Johnson)

  • Daniel Knowland

    (Janssen Pharmaceutical Companies of Johnson and Johnson)

  • Hong Yu

    (Janssen Pharmaceutical Companies of Johnson and Johnson)

  • Shenyan Gu

    (Janssen Pharmaceutical Companies of Johnson and Johnson)

  • David S. Bredt

    (Janssen Pharmaceutical Companies of Johnson and Johnson)

Abstract

Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide screening, we find that SAT1 selectively controls nicotinic acetylcholine receptor (nAChR) biogenesis. SAT1 specifically augments assembly of nAChRs containing α7 or α4β2, but not α6 subunits. Polyamines are classically studied as regulators of ion channel gating that engage the nAChR channel pore. In contrast, we find polyamine effects on assembly involve the nAChR cytosolic loop. Neurological studies link brain polyamines with neurodegenerative conditions. Our pharmacological and transgenic animal studies find that reducing polyamines enhances cortical neuron nAChR expression and augments nicotine-mediated neuroprotection. Taken together, we describe a most unexpected role for polyamines in regulating ion channel assembly, which provides a new avenue for nAChR neuropharmacology.

Suggested Citation

  • Madhurima Dhara & Jose A. Matta & Min Lei & Daniel Knowland & Hong Yu & Shenyan Gu & David S. Bredt, 2020. "Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16629-3
    DOI: 10.1038/s41467-020-16629-3
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