Potential oligomeric organizations of TMEM16 Cl⁻ channels. View from the extracellular space looking down on the membrane. (A) TMEM16A is represented as two gray subunits that dimerize back to back like nhTMEM16 via interaction between extended N and C termini and between TMDs at the interface. Each subunit adopts an open conformation when Ca²⁺ ions (not depicted) bind. The pore for Cl⁻ ions (green spheres) is formed in the space between the head groups of phospholipids (orange spheres) and the grooved aqueduct on the outer surface of each subunit. (B) Alternatively, cavities (white circles) at the dimer interface similar to those in the nhTMEM16 structure may form the Cl⁻ permeation pathway. (C) TMEM16A may dimerize differently than nhTMEM16, aqueduct to aqueduct, creating a central, protein-lined ion pore. Dimerization occurs via homotypic interaction between N termini. Two Cl⁻ ions are shown in the pore to suggest that this pore has dual pore characteristics.