Voltage and pH difference across the membrane control the S4 voltage-sensor motion of the Hv1 proton channel

The voltage-gated proton channel Hv1 is expressed in a variety of cells, including macrophages, sperm, and lung epithelial cells. Hv1 is gated by both the membrane potential and the difference between the intra- and extracellular pH (Delta pH). The coupling of voltage- and pH-sensing is such that Hv1 opens only when the electrochemical proton gradient is outwardly directed. However, the molecular mechanism of this coupling is not known. Here, we investigate the coupling between voltage- and Delta pH-sensing of Ciona intestinalis proton channel (ciHv1) using patch-clamp fluorometry (PCF) and proton uncaging. We show that changes in Delta pH can induce conformational changes of the S4 voltage sensor. Our results are consistent with the idea that S4 can detect both voltage and Delta pH.