Proposed functional mechanisms of TMEM16, OSCA/TMEM63, and TMC super family. (A) A shared proteo-lipidic conduit mediating ion conduction lined with lipid headgroups. OSCA/TMEM63s under membrane tension or TMEM16s with Ca2+ binding may undergo conformational changes that dilate a central ion-permeable pore lined by lipid headgroups and conserved hydrophilic residues. (B) Spatially competition of ion permeation and lipid translocation. Ion permeation and lipid translocation may occur through physically distinct but allosterically coupled pathways in TMEM16s. TMC1 may employ a stepwise activation mechanism, such that subsequently shifting TM4 and TM6 may laterally drag the pore lipid headgroups to line the ion permeable pathway instead of blocking it.