Forward genetic screen links EAG potassium channel domain interface to sleep regulation

Researchers at the University of Wisconsin-Madison, publishing in PLOS Genetics, used an unbiased forward genetic screen in the nematode Caenorhabditis elegans to identify a gain-of-function mutation in EGL-2, a member of the EAG-subfamily of KCNH voltage-gated potassium channels, that suppresses sleep behaviour.

The mutation — G574E — alters a highly conserved glycine residue at the interface between cyclic nucleotide-binding homology domains (CNBHDs) of adjacent channel subunits. CNBHDs are a hallmark structural feature of the KCNH family, but their precise role in gating and in downstream behavioural regulation had remained unclear. The authors demonstrate that EGL-2 functions in a cell-autonomous manner and that the CNBHD-CNBHD interface acts to restrain channel activation under normal conditions; disrupting this interface via G574E prolongs channel activity and thereby suppresses sleep.

KCNH channels are conserved from nematodes to humans, and human family members — including hERG (KCNH2), EAG1 (KCNH1), and EAG2 (KCNH5) — are implicated in cardiac arrhythmia, neurological conditions, and neurodevelopmental disorders. The study illustrates how forward genetics in a simple model organism can reveal conserved structural mechanisms with potential broader relevance to ion-channel biology. The paper is peer reviewed and published in PLOS Genetics.