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Nat Commun May 10, 2018; 9 (1): 1847.
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Direct neurotransmitter activation of voltage-gated potassium channels.

Manville RW , Papanikolaou M , Abbott GW .

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.

PubMed ID: 29748663
PMC ID: PMC5945843
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: drg1 gabarap kcna1 kcne1 kcnq1 kcnq2 kcnq3 kcnq5 ngf

Article Images: [+] show captions
References [+] :
Altschul, Basic local alignment search tool. 1990, Pubmed