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

Madhurima Dhara, Jose A. Matta, Min Lei, Daniel Knowland, Hong Yu, Shenyan Gu and David S. Bredt ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16629-3

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