The intracellular subdomain of the volume-regulated anion channel subunit LRRC8A is a hotspot of channel activation.

Mutations in the intracellular subdomain of LRRC8A cause constitutive activation of VRAC channels, highlighting its role as a key regulatory hub.

• Why it matters: Understanding how VRAC channels open and close is crucial because they regulate ion and osmolyte transport in many physiological processes, yet their gating mechanism remains unclear.
• What they did: The study used mutagenesis, FRET, and cryo-EM to analyze the ISD of LRRC8A, identifying mutations like L402W that make channels constitutively active and revealing conformational changes linked to gating.
• The result: Findings demonstrate that the ISD transmits conformational signals from LRRDs to the pore, enabling targeted modulation of VRAC activity and advancing knowledge of channel regulation.