Regulation of epithelial tight junction permeability by cyclic AMP

In "leaky" epithelia, ions move through both a transcellular and a paracellular (serial alignment of tight junction and intercellular space) path. The efficiency of transepithelial transport could therefore be regulated if the cell was able to alter reversibly the permeability of tight junctions. (These are specialized regions of the apical cell membranes common to all epithelia.) We now report that such a mechanism indeed exists in the Necturus gallbladder. It is effected by cyclic AMP, which is already known to mediate surface membrane phenomena in a variety of cell systems through its interaction with the cytoskeletal system^1,2. In gallbladders mounted and perfused with electrolyte solutions in an Ussing-type chamber, exposure of the mucosal surface to cyclic AMP analogues increased transepithelial electrical resistance, potential difference and short-circuit current and decreased NaCl dilution potentials in a rapid and reversible manner. We also observed rapid depolarization of cell membrane electrical potentials and a slow decline in intracellular K⁺ activity. Freeze-fracture electron microscopy of tissues fixed with glutaraldehyde during the peak electrical response showed a reorientation of intramembranous junctional fibrils, suggesting that cyclic AMP reduces the ionic permeability of the paracellular pathway in this epithelium by altering the structure of tight junctions.