scholarly journals Molecular mechanism of Zn2+ inhibition of a voltage-gated proton channel

2016 ◽  
Vol 113 (40) ◽  
pp. E5962-E5971 ◽  
Author(s):  
Feng Qiu ◽  
Adam Chamberlin ◽  
Briana M. Watkins ◽  
Alina Ionescu ◽  
Marta Elena Perez ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Reproductive Tract ◽  
Voltage Sensor ◽  
Female Reproductive Tract ◽  
Proton Channel ◽  
Ph Homeostasis ◽  
Voltage Gated ◽  
Gate Opening ◽  
Future Drug ◽  
High Concentrations

Voltage-gated proton (Hv1) channels are involved in many physiological processes, such as pH homeostasis and the innate immune response. Zn2+ is an important physiological inhibitor of Hv1. Sperm cells are quiescent in the male reproductive system due to Zn2+ inhibition of Hv1 channels, but become active once introduced into the low-Zn2+-concentration environment of the female reproductive tract. How Zn2+ inhibits Hv1 is not completely understood. In this study, we use the voltage clamp fluorometry technique to identify the molecular mechanism of Zn2+ inhibition of Hv1. We find that Zn2+ binds to both the activated closed and resting closed states of the Hv1 channel, thereby inhibiting both voltage sensor motion and gate opening. Mutations of some Hv1 residues affect only Zn2+ inhibition of the voltage sensor motion, whereas mutations of other residues also affect Zn2+ inhibition of gate opening. These effects are similar in monomeric and dimeric Hv1 channels, suggesting that the Zn2+-binding sites are localized within each subunit of the dimeric Hv1. We propose that Zn2+ binding has two major effects on Hv1: (i) at low concentrations, Zn2+ binds to one site and prevents the opening conformational change of the pore of Hv1, thereby inhibiting proton conduction; and (ii) at high concentrations, Zn2+, in addition, binds to a second site and inhibits the outward movement of the voltage sensor of Hv1. Elucidating the molecular mechanism of how Zn2+ inhibits Hv1 will further our understanding of Hv1 function and might provide valuable information for future drug development for Hv1 channels.

Pharmacological modulation of voltage-gated sodium (NaV) channels alters nociception arising from the female reproductive tract

Pain ◽  
2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Joel Castro ◽  
Jessica Maddern ◽  
Andelain Erickson ◽  
Ashlee Caldwell ◽  
Luke Grundy ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Voltage Gated ◽  
Pharmacological Modulation ◽  
Nav Channels

scholarly journals Functionality of the voltage-gated proton channel truncated in S4

2009 ◽  
Vol 107 (5) ◽  
pp. 2313-2318 ◽  
Author(s):  
Souhei Sakata ◽  
Tatsuki Kurokawa ◽  
Morten H. H. Nørholm ◽  
Masahiro Takagi ◽  
Yoshifumi Okochi ◽  
...  
Keyword(s):  
Voltage Sensor ◽  
Proton Channel ◽  
Voltage Sensing ◽  
Proton Channels ◽  
Voltage Gated ◽  
Transmembrane Segments ◽  
Cysteine Scanning ◽  
Dog Pancreas ◽  
Voltage Gated Ion Channels ◽  
Channel Properties

The voltage sensor domain (VSD) is the key module for voltage sensing in voltage-gated ion channels and voltage-sensing phosphatases. Structurally, both the VSD and the recently discovered voltage-gated proton channels (Hv channels) voltage sensor only protein (VSOP) and Hv1 contain four transmembrane segments. The fourth transmembrane segment (S4) of Hv channels contains three periodically aligned arginines (R1, R2, R3). It remains unknown where protons permeate or how voltage sensing is coupled to ion permeation in Hv channels. Here we report that Hv channels truncated just downstream of R2 in the S4 segment retain most channel properties. Two assays, site-directed cysteine-scanning using accessibility of maleimide-reagent as detected by Western blotting and insertion into dog pancreas microsomes, both showed that S4 inserts into the membrane, even if it is truncated between the R2 and R3 positions. These findings provide important clues to the molecular mechanism underlying voltage sensing and proton permeation in Hv channels.

Role of Zinc in Fertility and Fecundity in the Rat

1958 ◽  
Vol 193 (3) ◽  
pp. 505-508 ◽  
Author(s):  
Samuel A. Gunn ◽  
Thelma Clark Gould
Keyword(s):  
Deleterious Effect ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
High Concentrations

It has been previously shown that zinc is present in high concentrations in the dorsolateral prostate of the rat (Mawson, C. A. and M. I. Fischer. Nature, London 167: 859, 1951) and that administered Zn65 is selectively taken up by that accessory sex gland (Gunn, S. A., T. C. Gould et al. Proc. Soc. Exper. Biol. & Med. 88: 556, 1955). This paper demonstrates that Zn65 traverses the entire female reproductive tract after ejaculation. The removal of large amounts of zinc from the ejaculate, by dorsolateral prostatectomy, has no deleterious effect on either fertility or fecundity.

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

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
T. Moritz Schladt ◽  
Thomas K. Berger
Keyword(s):  
Membrane Potential ◽  
Patch Clamp ◽  
Conformational Changes ◽  
Voltage Sensor ◽  
Lung Epithelial Cells ◽  
Proton Channel ◽  
Ph Sensing ◽  
Voltage Gated ◽  
Lung Epithelial ◽  
The Difference

AbstractThe 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 (ΔpH). 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 ΔpH-sensing of Ciona intestinalis proton channel (ciHv1) using patch-clamp fluorometry (PCF) and proton uncaging. We show that changes in ΔpH can induce conformational changes of the S4 voltage sensor. Our results are consistent with the idea that S4 can detect both voltage and ΔpH.

scholarly journals KCNE3 acts by promoting voltage sensor activation in KCNQ1

2015 ◽  
Vol 112 (52) ◽  
pp. E7286-E7292 ◽  
Author(s):  
Rene Barro-Soria ◽  
Marta E. Perez ◽  
H. Peter Larsson
Keyword(s):  
Electrostatic Interaction ◽  
Voltage Dependence ◽  
Voltage Sensor ◽  
Α Subunit ◽  
Voltage Range ◽  
Voltage Gated ◽  
Gate Opening ◽  
Channel Gate ◽  
Sensor Activation ◽  
Voltage Sensing Domain

KCNE β-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the colon, stomach, and kidney, KCNE3 coassembles with the α-subunit KCNQ1 to form K+ channels important for K+ and Cl− secretion that appear to be voltage-independent. How KCNE3 subunits turn voltage-gated KCNQ1 channels into apparent voltage-independent KCNQ1/KCNE3 channels is not completely understood. Different mechanisms have been proposed to explain the effect of KCNE3 on KCNQ1 channels. Here, we use voltage clamp fluorometry to determine how KCNE3 affects the voltage sensor S4 and the gate of KCNQ1. We find that S4 moves in KCNQ1/KCNE3 channels, and that inward S4 movement closes the channel gate. However, KCNE3 shifts the voltage dependence of S4 movement to extreme hyperpolarized potentials, such that in the physiological voltage range, the channel is constitutively conducting. By separating S4 movement and gate opening, either by a mutation or PIP2 depletion, we show that KCNE3 directly affects the S4 movement in KCNQ1. Two negatively charged residues of KCNE3 (D54 and D55) are found essential for the effect of KCNE3 on KCNQ1 channels, mainly exerting their effects by an electrostatic interaction with R228 in S4. Our results suggest that KCNE3 primarily affects the voltage-sensing domain and only indirectly affects the gate.

scholarly journals Molecular Mechanism of Zinc Inhibition on Voltage-Gated Proton Channel Hv1

2015 ◽  
Vol 108 (2) ◽  
pp. 367a
Author(s):  
Feng Qiu ◽  
Adam Chamberlin ◽  
Sergei Noskov ◽  
H. Peter Larsson
Keyword(s):  
Molecular Mechanism ◽  
Proton Channel ◽  
Voltage Gated ◽  
Zinc Inhibition

scholarly journals An electrostatic potassium channel opener targeting the final voltage sensor transition

2011 ◽  
Vol 137 (6) ◽  
pp. 563-577 ◽  
Author(s):  
Sara I. Börjesson ◽  
Fredrik Elinder
Keyword(s):  
Ion Channels ◽  
Epileptic Seizures ◽  
Voltage Sensor ◽  
K Channel ◽  
Voltage Gated ◽  
Pharmacological Mechanism ◽  
Channel Opening ◽  
Channel Surface ◽  
Future Drug ◽  
Voltage Gated Ion Channels

Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction between PUFA and ion channels are not well understood. In this study, we have localized the site of action for PUFAs on the voltage-gated Shaker K channel by introducing positive charges on the channel surface, which potentiated the PUFA effect. Furthermore, we found that PUFA mainly affects the final voltage sensor movement, which is closely linked to channel opening, and that specific charges at the extracellular end of the voltage sensor are critical for the PUFA effect. Because different voltage-gated K channels have different charge profiles, this implies channel-specific PUFA effects. The identified site and the pharmacological mechanism will potentially be very useful in future drug design of small-molecule compounds specifically targeting neuronal and cardiac excitability.

scholarly journals Dimer interaction in the Hv1 proton channel

2020 ◽  
Vol 117 (34) ◽  
pp. 20898-20907
Author(s):  
Laetitia Mony ◽  
David Stroebel ◽  
Ehud Y. Isacoff
Keyword(s):  
Functional Analysis ◽  
Ion Channel ◽  
Coiled Coil ◽  
Voltage Sensor ◽  
Proton Channel ◽  
Dimer Interface ◽  
Voltage Sensors ◽  
Voltage Gated ◽  
Channel Opening ◽  
The Stability

The voltage-gated proton channel Hv1 is a member of the voltage-gated ion channel superfamily, which stands out in design: It is a dimer of two voltage-sensing domains (VSDs), each containing a pore pathway, a voltage sensor (S4), and a gate (S1) and forming its own ion channel. Opening of the two channels in the dimer is cooperative. Part of the cooperativity is due to association between coiled-coil domains that extend intracellularly from the S4s. Interactions between the transmembrane portions of the subunits may also contribute, but the nature of transmembrane packing is unclear. Using functional analysis of a mutagenesis scan, biochemistry, and modeling, we find that the subunits form a dimer interface along the entire length of S1, and also have intersubunit contacts between S1 and S4. These interactions exert a strong effect on gating, in particular on the stability of the open state. Our results suggest that gating in Hv1 is tuned by extensive VSD–VSD interactions between the gates and voltage sensors of the dimeric channel.

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