Direct neurotransmitter activation of voltage-gated potassium channels

Rían W. Manville, Maria Papanikolaou and Geoffrey W. Abbott ()
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Rían W. Manville: ZOT 4560, School of Medicine, University of California
Maria Papanikolaou: ZOT 4560, School of Medicine, University of California
Geoffrey W. Abbott: ZOT 4560, School of Medicine, University of California

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Voltage-gated potassium channels KCNQ2–5 generate the M-current, which controls neuronal excitability. KCNQ2–5 subunits each harbor a high-affinity anticonvulsant drug-binding pocket containing an essential tryptophan (W265 in human KCNQ3) conserved for >500 million years, yet lacking a known physiological function. Here, phylogenetic analysis, electrostatic potential mapping, in silico docking, electrophysiology, and radioligand binding assays reveal that the anticonvulsant binding pocket evolved to accommodate endogenous neurotransmitters including γ-aminobutyric acid (GABA), which directly activates KCNQ5 and KCNQ3 via W265. GABA, and endogenous metabolites β-hydroxybutyric acid (BHB) and γ-amino-β-hydroxybutyric acid (GABOB), competitively and differentially shift the voltage dependence of KCNQ3 activation. Our results uncover a novel paradigm: direct neurotransmitter activation of voltage-gated ion channels, enabling chemosensing of the neurotransmitter/metabolite landscape to regulate channel activity and cellular excitability.

Date: 2018
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DOI: 10.1038/s41467-018-04266-w

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