 PDE5 is expressed in human colonic cells and in intestinal tissue and its activity is regulated by intracellular cGMP levels in these cells that increase on GCC activation.This presumably occurs through binding of cGMP to the GAF domains in the N-terminus of PDE5, resulting in allosteric activation of the enzyme.The mechanism of action of E4021 on both the nonactivated and activated forms of rod PDE6 because both states are relevant to understanding how PDE5-selective inhibitors may alter signal transduction pathways in photoreceptor cells.