Selectivity of the Voltage Gated Proton Channel HV1

Abstract

The voltage gated proton channel, HV1, triggers the flash in bioluminescent dinoflagellates, aids calcification by coccolithophores, and in humans, regulates pH in the respiratory tract, sperm capacitation, histamine secretion, the phagocyte respiratory burst, and B lymphocyte signaling. On the down-side, HV1 exacerbates breast cancer metastasis and brain damage from ischemic stroke. All of these functions require extreme proton selectivity, because [H+] is 106 lower than that of other ions. We studied proton selectivity in HV1 from humans and Karlodinium, a dinoflagellate, which share only 15% sequence identity. A crucial aspartate in the S1 transmembrane domain of each (Asp112 in hHV1, Asp51 in kHV1) is essential for proton selectivity; neutralizing mutations result in anion permeability or abolish conduction (Musset et al, 2011, Nature 480:273-277; Smith et al, 2011, Proc. Natl. Acad. Sci.U.S.A. 108:18162-18168). That the two proteins exhibit the same phenomenology despite limited sequence identity indicates that the selectivity mechanism is highly conserved. A combination of approaches, including accessibility studies of the three Arginine residues in the S4 helix, provides a picture of the open human HV1 channel, in which Arg205 (R1) is accessible to the external solution, Arg208 (R2) forms a salt bridge with Asp112, and Arg211 (R3) is accessible to the internal solution. Further studies of the molecular requirements for proton permeation and selectivity are underway.Support: NSF MCB-0943362, NIH R01-GM087507.