Large-pore channels such as pannexin-1 (PANX1) typically lack pore-lining constriction points, leaving only speculations on how these channels functionally "close." In this issue of Science Signaling, Kuzuya et al. found that rearrangements in the PANX1 amino-terminal helix mediate channel gating by a surprising mechanism in which lipids block the ion conduction pathway, creating a hydrophobic gate.