CFTR's multiple roles in fluid and electrolyte transport. (a) Salt absorption. In the sweat duct, high apical conductance for Na⁺ [1] and Cl^– [2] and relatively low water conductance allows salt to be reabsorbed in excess of water (hypertonic absorption) leaving a hypotonic luminal fluid. In the sweat duct CFTR is the only available anion conductance pathway, and when it is lost in CF the lumen quickly becomes highly electronegative and transport virtually ceases, resulting in high (similar to plasma) luminal salt (b). Fluid absorption. In epithelia with high water permeability [3] relative to electrolyte permeability water will absorbed osmotically with salt to decrease the volume of luminal fluid. If no other osmolytes or forces are present, the salt concentration will remain unchanged. If water-retaining forces are present, permeant electrolytes can be reduced preferentially. The consequences of eliminating CFTR depend on the magnitude of such forces, the relative magnitude of alternate pathways for transepithelial anion flow [4], and how CFTR affects other ion channels. The high salt and low volume hypotheses differ on each of these points. (c) Anion-mediated fluid secretion. Secreting epithelia lack a significant apical Na⁺ conductance. Basolateral transporters such as NKCC move Cl^– uphill into the cell; it then flows passively into the lumen via CFTR [5], K⁺ exits basolaterally, Na⁺ flows paracellularly [7] and water follows transcellularly [6]. Elimination of CFTR eliminates secretion.