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Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
- Source :
- Nature Communications, Nature Communications, Vol 11, Iss 1, Pp 1-12 (2020)
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.<br />Small molecule polyamines participate in diverse aspects of cell growth and differentiation and are known to regulate ion channel gating. Here authors reveal that cellular polyamines control nicotinic acetylcholine receptor (nAChR) biogenesis, and either catabolic degradation or inhibition of polyamine production augments nAChR assembly.
- Subjects :
- 0301 basic medicine
DNA, Complementary
Science
Cell death in the nervous system
General Physics and Astronomy
Receptors, Nicotinic
Neuroprotection
Article
Fluorescence
Ion Channels
Protein Structure, Secondary
General Biochemistry, Genetics and Molecular Biology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Acetyltransferases
Polyamines
Animals
Humans
Protein folding
lcsh:Science
Ion channel
Neuropharmacology
Neurons
Multidisciplinary
Genome, Human
General Chemistry
Molecular biophysics
Cellular neuroscience
Rats
Cell biology
Spermidine
Protein Subunits
Polyamine Catabolism
Nicotinic acetylcholine receptor
Enhancer Elements, Genetic
HEK293 Cells
030104 developmental biology
nervous system
chemistry
Biocatalysis
lcsh:Q
Polyamine
Ion Channel Gating
030217 neurology & neurosurgery
Biogenesis
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....b9c8317cecf97f19838a7b987ac76dd4