Activation of mouse Otop3 proton channels by Zn²

Otopetrins (Otop1-Otop3) belong to a newly identified family of proton (H⁺) channels activated by extracellular acidification. Here, we found that Zn²⁺ activates the mouse Otop3 (mOtop3) proton channels by using electrophysiological patch-clamp techniques. In mOtop3-expressing human embryonic kidney HEK293T cells, a biphasic inward mOtop3 H⁺ current comprising a fast transient current followed by a sustained current was observed upon extracellular acidification at pH 5.0. No significant activation of the mOtop3 channel was observed at pH 6.5 and 7.4, but interestingly, Zn²⁺ dose-dependently induced a sustained activation of mOtop3 under these pH conditions. Increasing the Zn²⁺ concentration had no effect on the reversal potential of the channel currents, suggesting that Zn²⁺ does not permeate through the mOtop3. The activation of the mOtop3 channel was specific to Zn²⁺ among divalent metal cations. Our findings reveal a novel modulatory mechanism of mOtop3 proton channels by Zn²⁺.