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<p>Strains used in this study.</p>

Listed in UCL Research Data Repository and HKU DataHub and Swinburne Figshare and DaYta Ya Rona and SUNScholarData and figshare and Loughborough Research Repository and GRANTS Data and UP Research Data Repository — shown once because both records carry DOI 10.1371/journal.pgen.1012255.s005

<div><p>KCNH voltage-gated potassium channels regulate neuronal excitability, yet how their hallmark cyclic nucleotide-binding homology domains (CNBHDs) influence channel gating to regulate behavior remains unclear.

Description

Using an unbiased forward genetic screen in <i>Caenorhabditis elegans</i>, we identified a gain-of-function mutation in the EAG-subfamily KCNH channel EGL-2 that suppresses sleep. The mutation (G574E) alters a highly conserved glycine residue at the interface between CNBHDs of adjacent channel subunits.

EGL-2 functions cell-autonomously in the central sleep-promoting neuron ALA. <i>In vivo</i> calcium imaging showed that the gain-of-function mutation suppresses sleep by inhibiting ALA neuronal activity, consistent with enhanced potassium channel activity. Genetic analysis demonstrated that the sleep-suppressing phenotype of G574E requires both an intact potassium selectivity filter and the intrinsic ligand-occupied CNBHD.

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A second substitution at the same glycine (G574R), which introduces a positively charged side chain in contrast to the negatively charged side chain in G574E, similarly suppresses sleep, indicating that perturbation of the CNBHD-CNBHD interface, rather than the specific amino acid change, underlies the phenotype. Moreover, mutations at the corresponding residue in the ERG-subfamily KCNH channels <i>C. elegans</i> UNC-103 and human hERG also produce gain-of-function effects, and electrophysiological analysis showed that hERG(G749R) shifts voltage-dependent channel activation to more negative potentials and accelerates activation kinetics.

These findings identify EGL-2 as an important sleep regulator and uncover a conserved molecular mechanism by which the CNBHD-CNBHD interface restrains KCNH channel activation to regulate neuronal excitability and behavior.</p></div>

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Astronomy & Astrophysics · Biochemistry and cell biology · Biochemistry and cell biology · Biochemistry and cell biology · Biochemistry and cell biology · Biochemistry and cell biology · Biochemistry and cell biology · Biochemistry and cell biology · Biochemistry and cell biology · Biochemistry and cell biology · Caenorhabditis elegans · Caenorhabditis elegans · Caenorhabditis elegans · Caenorhabditis elegans · Caenorhabditis elegans · Caenorhabditis elegans · Caenorhabditis elegans · Caenorhabditis elegans · Caenorhabditis elegans · Cancer · Cancer · Cancer · Cancer · Cancer · Cancer · Cancer · Cancer · Cancer · Chemistry · Chemistry · Computer Science & AI · Computer Science & AI · Earth & Environmental Science · Earth & Environmental Science · Earth & Environmental Science · Earth & Environmental Science · Earth & Environmental Science · Earth & Environmental Science · Earth & Environmental Science · Earth & Environmental Science · Earth & Environmental Science · Economics & Finance · Economics & Finance · Engineering · Engineering · Engineering · Engineering · Genetics · Genetics · Genetics · Genetics · Genetics · Genetics · Genetics · Genetics · Genetics · Humanities · Humanities · Humanities · Humanities · Life Sciences · Life Sciences · Life Sciences · Life Sciences · Life Sciences · Life Sciences · Life Sciences · Life Sciences · Life Sciences · Materials Science · Mathematics & Statistics · Medicine & Health · Medicine & Health · Medicine & Health · Medicine & Health · Medicine & Health · Medicine & Health · Medicine & Health · Medicine & Health · Medicine & Health · Ocean & Atmospheric Science · Psychology & Behavioral Science · Social Science · Social Science · Social Science · Social Science
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Provenance · 9 source records, 92 field assertions
SourceKeyLast seenRaw
UCL Research Data Repositoryoai:figshare.com:article/340495128 d agoJSON v1
HKU DataHuboai:figshare.com:article/340495127 d agoJSON v1
Swinburne Figshareoai:figshare.com:article/340495127 d agoJSON v1
DaYta Ya Ronaoai:figshare.com:article/340495127 d agoJSON v1
SUNScholarDataoai:figshare.com:article/340495127 d agoJSON v1
figshareoai:figshare.com:article/340495127 d agoJSON v1
Loughborough Research Repositoryoai:figshare.com:article/340495127 d agoJSON v1
GRANTS Dataoai:figshare.com:article/340495127 d agoJSON v1
UP Research Data Repositoryoai:figshare.com:article/340495126 d agoJSON v1
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