| First Author | Manville RW | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 1847 |
| PubMed ID | 29748663 | Mgi Jnum | J:262937 |
| Mgi Id | MGI:6161044 | Doi | 10.1038/s41467-018-04266-w |
| Citation | Manville RW, et al. (2018) Direct neurotransmitter activation of voltage-gated potassium channels. Nat Commun 9(1):1847 |
| abstractText | 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 gamma-aminobutyric acid (GABA), which directly activates KCNQ5 and KCNQ3 via W265. GABA, and endogenous metabolites beta-hydroxybutyric acid (BHB) and gamma-amino-beta-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. |
