Forward genetics reveals a conserved CNBHD-CNBHD interface that restrains EAG channel activation to regulate sleep.

A conserved CNBHD-CNBHD interface in KCNH channels restrains activation to regulate sleep, with mutations causing gain-of-function effects in C. elegans and humans.

• Why it matters: Understanding how KCNH channels influence neuronal excitability and sleep regulation remains incomplete, limiting insights into behavior control mechanisms across species.
• What they did: Using an unbiased forward genetic screen in Caenorhabditis elegans, the study identified mutations at a conserved glycine residue in EGL-2 that suppress sleep by enhancing potassium channel activity, with similar effects observed in human hERG channels.
• The result: Mutations at the CNBHD-CNBHD interface increase channel activity and shift voltage-dependent activation to more negative potentials, revealing a conserved mechanism that restrains KCNH channel activation to regulate neuronal excitability and sleep behavior.