The Voltage-Gated Proton Channel Hv1 Has Two Pores, Each Controlled by One Voltage Sensor

Abstract

In voltage-gated channels, ions flow through a single pore located at the interface between membrane-spanning pore domains from each of four subunits, and the gates of the pore are controlled by four peripheral voltage-sensing domains. In a striking exception, the newly discovered voltage-gated Hv1 proton channels lack a homologous pore domain, leaving the location of the pore unknown. Also unknown are the number of subunits and the mechanism of gating. We find that Hv1 is a dimer and that each subunit contains its own pore and gate, which is controlled by its own voltage sensor. Our experiments show that the cytosolic domain of the channel is necessary and sufficient for dimerization and that the transmembrane part of the channel is functional also when monomerized. The results suggest a mechanism of gating whereby the voltage sensor and gate are one and the same.

Flagellar ion channels of sperm: similarities and differences between species

“…Hv1 forms a functional dimer in the plasma membrane through a coil-coil interaction of the C-termini [128][129][130]; though, each Hv1 subunit can function independently as a channel. Mutations in Hv1 appear to be extremely rare with only one case of a single substitution mutation being reported in humans [131], which was assessed only in airway epithelial cells.…”

The cytoplasmic coiled-coil mediates cooperative gating temperature sensitivity in the voltage-gated H+ channel Hv1

“…Hv1/VSOP has fourtransmembrane segments that correspond to the voltage-sensor domain (S1-S4) of other voltage-gated channels 1,2 , it does not have a canonical pore domain, and the voltage-sensor domain is thought to act as both the voltage-sensor and the H + -permeation pathway 7 . The composition of the functional unit by the minimally designed voltage-gated channel subunit is dimeric [8][9][10] .…”

“…Assembly of the four subunits into the tetrameric channel forms the permeation pathway in the centre. In the Hv channel, by contrast, only one subunit of the dimeric functional unit is sufficient for its channel activity 8,10 . The functional role of dimer formation, hence, lies outside the formation of the permeation pathway.…”

Grafting voltage and pharmacological sensitivity in potassium channels

“…Notably, the S4-S5 linker is not required for voltage-dependent gating of KCNH potassium channels, suggesting that the voltage sensing could be transduced between the pore and VSD modules in the absence of covalent linker [47]. Although a single VSD can sense the changes of membrane potential and function independently [48][49][50], swapping the full-length VSD among 4-fold symmetric voltage-sensitive channels or transplanting the full-length VSD to the monomeric VSP failed to obtain functional proteins [40,51]. In our study, grafting the full-length VSDs, together with the upstream N-terminus and the downstream S4-S5 linker, to the host protein as an integral module produced functional voltage-gated channels, extending our understanding of the modularity of VSD.…”