The transient receptor potential channel TRPV6 is located in the polarized epithelia at small intestine, kidney, placenta, prostate, pancreas, etc. It is known that it is also localized to the skin but few scientists were interested in it because the pH change in the internal organs in human body is rare. However, it was reported recently that the calcium level in skin epithelium plays an important role for wound healing and aging. It means TRPV6 at skin epithelium has a possibility that it is in charge of the regulation of Ca2+ homeostasis. We now report the function of TRPV6 is inhibited by internal and external protons. As we could guess on the basis of the amino acid sequences glutamate-521 of the extracellular region has a critical activity as an extracellular proton sensor. The pKa of TRPV6 was about 7.5. To confirm the intracellular proton sensor we used inside-out patches. Intracellular acidification also decreased the channel activity and the kinetics were bigger than extracellular one. We determined the intracellular and extracellular protons cross-regulate TRPV6 and such a regulation by acidification underlies pathogenesis of desturbances of Ca2+ transport in many diseased states.