An oxygen-sensitive mechanism in regulation of epithelial sodium channel

Epithelial sodium channels (ENaCs) are of immense importance, controlling Na+ transport across epithelia and thus playing a central role in all aspects of fluid clearance as well as numerous other functions. Regulation of these channels is critical. Here, we show that haem, a regulator of Na+ transport, directly influences ENaC activity, decreasing channel-open probability (but not unitary conductance) in inside-out patches (but not outside-out). Conversely, exposure to the protein in the presence of NADPH and at normoxic O-2 tension (requirements for activity of hemeoxygenase) increases channel activity. CO, a product of hemeoxygenase activity, activated ENaC in a manner similar to that of haem plus NADPH. However, under hypoxic conditions, inhibition of ENaC by haem occurred even in the presence of NADPH. These data demonstrate a potent, O-2-sensitive mechanism for regulation of ENaC, in which hemeoxygenase acts as the O-2 sensor, its substrate and product inhibiting and stimulating (respectively) the activity of ENaC.