The fundamental role of HVCN1 is to pump out protons, thereby increasing the intracellular pH. The channel is exclusively selective for H+ and opens upon membrane depolarization, although its open state hugely depends on the pH on both sides of the membrane4. Its role is best described in leukocytes where phosphorylation via PKC on a Thr residue potentiates the activity of the channel and increases its open state, thereby increasing the H+ current across the membrane, in this manner mediating optimal NADPH-oxidase (whose optimal activity is at pH 7.5) required for the production of reactive oxygen species (ROS) necessary for phagocytosis to occur.nApart from leukocytes, HVCN1 is also expressed in basophils where its activation mediates histamine release. In B cells, it maintains optimal signaling, such that ROS production is maintained high10. HVCN1 was found to regulate human spermatozoa activation. Finally, in the airway mucosa, where it regulates pH, channel gating there, is mostly mediated by differences in pH across the membrane as opposed to the membrane potential.