Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 312 (5773): 589-592

Copyright © 2006 by the American Association for the Advancement of Science

A Voltage Sensor-Domain Protein Is a Voltage-Gated Proton Channel

Mari Sasaki,1,2,3 Masahiro Takagi,1,3 Yasushi Okamura1,2,3,4*

Abstract: Voltage-gated proton channels have been widely observed but have not been identified at a molecular level. Here we report that a four-transmembrane protein similar to the voltage-sensor domain of voltage-gated ion channels is a voltage-gated proton channel. Cells overexpressing this protein showed depolarization-induced outward currents accompanied by tail currents. Current reversal occured at equilibrium potentials for protons. The currents exhibited pH-dependent gating and zinc ion sensitivity, two features which are characteristic of voltage-gated proton channels. Responses of voltage dependence to sequence changes suggest that mouse voltage-sensor domain–only protein is itself a channel, rather than a regulator of another channel protein.

1 Section of Developmental Neurophysiology, Okazaki Institute for Integrative Bioscience, Higashiyama 5-1, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan.
2 The Graduate University for Advanced Studies, Higashiyama 5-1, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan.
3 National Institute for Physiological Sciences, National Institutes of Natural Sciences, Higashiyama 5-1, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan.
4 Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba Central 6, Higashi 1-1-1, Tsukuba, Ibaraki 305-8566, Japan.

Note added in proof: D. Clapham's laboratory reports similar properties of a human ortholog, Hv1 (22).

* To whom correspondence should be addressed. E-mail: yokamura{at}nips.ac.jp

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Voltage-Gated Proton Channels: Molecular Biology, Physiology, and Pathophysiology of the HV Family.
T. E. DeCoursey (2013)
Physiol Rev 93, 599-652
   Abstract »    Full Text »    PDF »
Construction and validation of a homology model of the human voltage-gated proton channel hHV1.
K. Kulleperuma, S. M. E. Smith, D. Morgan, B. Musset, J. Holyoake, N. Chakrabarti, V. V. Cherny, T. E. DeCoursey, and R. Pomes (2013)
J. Gen. Physiol. 141, 445-465
   Abstract »    Full Text »    PDF »
Molecular mechanism of voltage sensing in voltage-gated proton channels.
C. Gonzalez, S. Rebolledo, M. E. Perez, and H. P. Larsson (2013)
J. Gen. Physiol. 141, 275-285
   Abstract »    Full Text »    PDF »
Voltage sensor ring in a native structure of a membrane-embedded potassium channel.
L. Shi, H. Zheng, H. Zheng, B. A. Borkowski, D. Shi, T. Gonen, and Q.-X. Jiang (2013)
PNAS 110, 3369-3374
   Abstract »    Full Text »    PDF »
Gating of the designed trimeric/tetrameric voltage-gated H+ channel.
Y. Fujiwara, T. Kurokawa, K. Takeshita, A. Nakagawa, H. P. Larsson, and Y. Okamura (2013)
J. Physiol. 591, 627-640
   Abstract »    Full Text »    PDF »
Intermediate state trapping of a voltage sensor.
J. J. Lacroix, S. A. Pless, L. Maragliano, F. V. Campos, J. D. Galpin, C. A. Ahern, B. Roux, and F. Bezanilla (2012)
J. Gen. Physiol. 140, 635-652
   Abstract »    Full Text »    PDF »
Evolution of the Voltage Sensor Domain of the Voltage-Sensitive Phosphoinositide Phosphatase VSP/TPTE Suggests a Role as a Proton Channel in Eutherian Mammals.
K. A. Sutton, M. K. Jungnickel, L. Jovine, and H. M. Florman (2012)
Mol. Biol. Evol. 29, 2147-2155
   Abstract »    Full Text »    PDF »
Lipopolysaccharide-sensitive H+ current in dendritic cells.
K. Szteyn, W. Yang, E. Schmid, F. Lang, and E. Shumilina (2012)
Am J Physiol Cell Physiol 303, C204-C212
   Abstract »    Full Text »    PDF »
Membrane bending is critical for the stability of voltage sensor segments in the membrane.
K. M. Callenberg, N. R. Latorraca, and M. Grabe (2012)
J. Gen. Physiol. 140, 55-68
   Abstract »    Full Text »    PDF »
Tracking a complete voltage-sensor cycle with metal-ion bridges.
U. Henrion, J. Renhorn, S. I. Borjesson, E. M. Nelson, C. S. Schwaiger, P. Bjelkmar, B. Wallner, E. Lindahl, and F. Elinder (2012)
PNAS 109, 8552-8557
   Abstract »    Full Text »    PDF »
Clinicopathological and Biological Significance of Human Voltage-gated Proton Channel Hv1 Protein Overexpression in Breast Cancer.
Y. Wang, S. J. Li, X. Wu, Y. Che, and Q. Li (2012)
J. Biol. Chem. 287, 13877-13888
   Abstract »    Full Text »    PDF »
Inhibition of voltage-gated proton channels by local anaesthetics in GMI-R1 rat microglia.
T. Matsuura, T. Mori, M. Hasaka, M. Kuno, J. Kawawaki, K. Nishikawa, T. Narahashi, M. Sawada, and A. Asada (2012)
J. Physiol. 590, 827-844
   Abstract »    Full Text »    PDF »
Voltage-gated proton channel in a dinoflagellate.
S. M. E. Smith, D. Morgan, B. Musset, V. V. Cherny, A. R. Place, J. W. Hastings, and T. E. DeCoursey (2011)
PNAS 108, 18162-18167
   Abstract »    Full Text »    PDF »
Phagosome dynamics during phagocytosis by neutrophils.
P. Nordenfelt and H. Tapper (2011)
J. Leukoc. Biol. 90, 271-284
   Abstract »    Full Text »    PDF »
Rediscovering sperm ion channels with the patch-clamp technique.
Y. Kirichok and P. V. Lishko (2011)
Mol. Hum. Reprod. 17, 478-499
   Abstract »    Full Text »    PDF »
Voltage-gated sodium channel (NaV) protein dissection creates a set of functional pore-only proteins.
D. Shaya, M. Kreir, R. A. Robbins, S. Wong, J. Hammon, A. Bruggemann, and D. L. Minor Jr. (2011)
PNAS 108, 12313-12318
   Abstract »    Full Text »    PDF »
Crystal Structure of the Cytoplasmic Phosphatase and Tensin Homolog (PTEN)-like Region of Ciona intestinalis Voltage-sensing Phosphatase Provides Insight into Substrate Specificity and Redox Regulation of the Phosphoinositide Phosphatase Activity.
M. Matsuda, K. Takeshita, T. Kurokawa, S. Sakata, M. Suzuki, E. Yamashita, Y. Okamura, and A. Nakagawa (2011)
J. Biol. Chem. 286, 23368-23377
   Abstract »    Full Text »    PDF »
Voltage-Sensing Phosphatase: Its Molecular Relationship With PTEN.
Y. Okamura and J. E. Dixon (2011)
Physiology 26, 6-13
   Abstract »    Full Text »    PDF »
A proton current drives action potentials in genetically identified sour taste cells.
R. B. Chang, H. Waters, and E. R. Liman (2010)
PNAS 107, 22320-22325
   Abstract »    Full Text »    PDF »
Physiological roles of voltage-gated proton channels in leukocytes.
N. Demaurex and A. El Chemaly (2010)
J. Physiol. 588, 4659-4665
   Abstract »    Full Text »    PDF »
The role of Hv1 and CatSper channels in sperm activation.
P. V. Lishko and Y. Kirichok (2010)
J. Physiol. 588, 4667-4672
   Abstract »    Full Text »    PDF »
Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating-modifier.
A. Peretz, L. Pell, Y. Gofman, Y. Haitin, L. Shamgar, E. Patrich, P. Kornilov, O. Gourgy-Hacohen, N. Ben-Tal, and B. Attali (2010)
PNAS 107, 15637-15642
   Abstract »    Full Text »    PDF »
Function of the HVCN1 proton channel in airway epithelia and a naturally occurring mutation, M91T.
D. Iovannisci, B. Illek, and H. Fischer (2010)
J. Gen. Physiol. 136, 35-46
   Abstract »    Full Text »    PDF »
Single or double? Think zinc!.
Y. Okamura (2010)
J. Physiol. 588, 1803-1804
   Full Text »    PDF »
Voltage-sensor mutations in channelopathies of skeletal muscle.
S. C. Cannon (2010)
J. Physiol. 588, 1887-1895
   Abstract »    Full Text »    PDF »
Zinc inhibition of monomeric and dimeric proton channels suggests cooperative gating.
B. Musset, S. M. E. Smith, S. Rajan, V. V. Cherny, S. Sujai, D. Morgan, and T. E. DeCoursey (2010)
J. Physiol. 588, 1435-1449
   Abstract »    Full Text »    PDF »
The Role and Structure of the Carboxyl-terminal Domain of the Human Voltage-gated Proton Channel Hv1.
S. J. Li, Q. Zhao, Q. Zhou, H. Unno, Y. Zhai, and F. Sun (2010)
J. Biol. Chem. 285, 12047-12054
   Abstract »    Full Text »    PDF »
A Gating Charge Transfer Center in Voltage Sensors.
X. Tao, A. Lee, W. Limapichat, D. A. Dougherty, and R. MacKinnon (2010)
Science 328, 67-73
   Abstract »    Full Text »    PDF »
The activated state of a sodium channel voltage sensor in a membrane environment.
S. Chakrapani, P. Sompornpisut, P. Intharathep, B. Roux, and E. Perozo (2010)
PNAS 107, 5435-5440
   Abstract »    Full Text »    PDF »
Permeation mechanism in voltage-activated proton channels: A new glimpse.
C. Gonzalez and H. P. Larsson (2010)
PNAS 107, 1817-1818
   Full Text »    PDF »
Functionality of the voltage-gated proton channel truncated in S4.
S. Sakata, T. Kurokawa, M. H. H. Norholm, M. Takagi, Y. Okochi, G. von Heijne, and Y. Okamura (2010)
PNAS 107, 2313-2318
   Abstract »    Full Text »    PDF »
Voltage-Gated Proton Channels Find Their Dream Job Managing the Respiratory Burst in Phagocytes.
T. E. DeCoursey (2010)
Physiology 25, 27-40
   Abstract »    Full Text »    PDF »
VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification.
A. El Chemaly, Y. Okochi, M. Sasaki, S. Arnaudeau, Y. Okamura, and N. Demaurex (2010)
J. Exp. Med. 207, 129-139
   Abstract »    Full Text »    PDF »
Architecture and gating of Hv1 proton channels.
F. Tombola, M. H. Ulbrich, and E. Y. Isacoff (2009)
J. Physiol. 587, 5325-5329
   Abstract »    Full Text »    PDF »
Temperature dependence of proton permeation through a voltage-gated proton channel.
M. Kuno, H. Ando, H. Morihata, H. Sakai, H. Mori, M. Sawada, and S. Oiki (2009)
J. Gen. Physiol. 134, 191-205
   Abstract »    Full Text »    PDF »
Hv1 proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst.
I. S. Ramsey, E. Ruchti, J. S. Kaczmarek, and D. E. Clapham (2009)
PNAS 106, 7642-7647
   Abstract »    Full Text »    PDF »
Voltage-sensing phosphatase: actions and potentials.
Y. Okamura, Y. Murata, and H. Iwasaki (2009)
J. Physiol. 587, 513-520
   Abstract »    Full Text »    PDF »
Molecular Template for a Voltage Sensor in a Novel K+ Channel. III. Functional Reconstitution of a Sensorless Pore Module from a Prokaryotic Kv Channel.
J. S. Santos, S. M. Grigoriev, and M. Montal (2008)
J. Gen. Physiol. 132, 651-666
   Abstract »    Full Text »    PDF »
Voltage-gated proton channels: what's next?.
T. E. DeCoursey (2008)
J. Physiol. 586, 5305-5324
   Abstract »    Full Text »    PDF »
Ion Channels in Microbes.
B. Martinac, Y. Saimi, and C. Kung (2008)
Physiol Rev 88, 1449-1490
   Abstract »    Full Text »    PDF »
Multimeric nature of voltage-gated proton channels.
H. P. Koch, T. Kurokawa, Y. Okochi, M. Sasaki, Y. Okamura, and H. P. Larsson (2008)
PNAS 105, 9111-9116
   Abstract »    Full Text »    PDF »
Enzyme Domain Affects the Movement of the Voltage Sensor in Ascidian and Zebrafish Voltage-sensing Phosphatases.
Md. I. Hossain, H. Iwasaki, Y. Okochi, M. Chahine, S. Higashijima, K. Nagayama, and Y. Okamura (2008)
J. Biol. Chem. 283, 18248-18259
   Abstract »    Full Text »    PDF »
Dimeric subunit stoichiometry of the human voltage-dependent proton channel Hv1.
S.-Y. Lee, J. A. Letts, and R. MacKinnon (2008)
PNAS 105, 7692-7695
   Abstract »    Full Text »    PDF »
Proton Conductivity through the Human TRPM7 Channel and Its Molecular Determinants.
T. Numata and Y. Okada (2008)
J. Biol. Chem. 283, 15097-15103
   Abstract »    Full Text »    PDF »
A mysterious channel: new insights into proton channel functioning raise new questions.
C. Eder (2008)
J. Physiol. 586, 2419-2420
   Full Text »    PDF »
Detailed comparison of expressed and native voltage-gated proton channel currents.
B. Musset, V. V. Cherny, D. Morgan, Y. Okamura, I. S. Ramsey, D. E. Clapham, and T. E. DeCoursey (2008)
J. Physiol. 586, 2477-2486
   Abstract »    Full Text »    PDF »
Exclusion of a Proton ATPase from the Apical Membrane Is Associated with Cell Polarity and Tip Growth in Nicotiana tabacum Pollen Tubes.
A. C. Certal, R. B. Almeida, L. M. Carvalho, E. Wong, N. Moreno, E. Michard, J. Carneiro, J. Rodriguez-Leon, H.-M. Wu, A. Y. Cheung, et al. (2008)
PLANT CELL 20, 614-634
   Abstract »    Full Text »    PDF »
Mapping the Membrane-aqueous Border for the Voltage-sensing Domain of a Potassium Channel.
E. J. Neale, H. Rong, C. J. Cockcroft, and A. Sivaprasadarao (2007)
J. Biol. Chem. 282, 37597-37604
   Abstract »    Full Text »    PDF »
Mg2+ mediates interaction between the voltage sensor and cytosolic domain to activate BK channels.
H. Yang, L. Hu, J. Shi, K. Delaloye, F. T. Horrigan, and J. Cui (2007)
PNAS 104, 18270-18275
   Abstract »    Full Text »    PDF »
Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2.
Y. Murata and Y. Okamura (2007)
J. Physiol. 583, 875-889
   Abstract »    Full Text »    PDF »
Expression of the Voltage-Gated Sodium Channel NaV1.5 in the Macrophage Late Endosome Regulates Endosomal Acidification.
M. D. Carrithers, S. Dib-Hajj, L. M. Carrithers, G. Tokmoulina, M. Pypaert, E. A. Jonas, and S. G. Waxman (2007)
J. Immunol. 178, 7822-7832
   Abstract »    Full Text »    PDF »
Bilayer deformation by the Kv channel voltage sensor domain revealed by self-assembly simulations.
P. J. Bond and M. S. P. Sansom (2007)
PNAS 104, 2631-2636
   Abstract »    Full Text »    PDF »
Development and Validation of Endogenous Reference Genes for Expression Profiling of Medaka (Oryzias latipes) Exposed to Endocrine Disrupting Chemicals by Quantitative Real-Time RT-PCR.
Z. Zhang and J. Hu (2007)
Toxicol. Sci. 95, 356-368
   Abstract »    Full Text »    PDF »
2006: Signaling Breakthroughs of the Year.
E. M. Adler, N. R. Gough, and L. B. Ray (2007)
Sci. STKE 2007, eg1
   Abstract »    Full Text »    PDF »
SK channels mediate NADPH oxidase-independent reactive oxygen species production and apoptosis in granulocytes.
A. J. Fay, X. Qian, Y. N. Jan, and L. Y. Jan (2006)
PNAS 103, 17548-17553
   Abstract »    Full Text »    PDF »
Molecular Template for a Voltage Sensor in a Novel K+ Channel. I. Identification and Functional Characterization of KvLm, a Voltage-gated K+ Channel from Listeria monocytogenes.
J. S. Santos, A. Lundby, C. Zazueta, and M. Montal (2006)
J. Gen. Physiol. 128, 283-292
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
(2006)
Physiology 21, 229-232
   Full Text »    PDF »
The Antibacterial Activity of Human Neutrophils and Eosinophils Requires Proton Channels but Not BK Channels.
J. K. Femling, V. V. Cherny, D. Morgan, B. Rada, A. P. Davis, G. Czirjak, P. Enyedi, S. K. England, J. G. Moreland, E. Ligeti, et al. (2006)
J. Gen. Physiol. 127, 659-672
   Abstract »    Full Text »    PDF »
Biophysics. Lonely voltage sensor seeks protons for permeation..
C. Miller (2006)
Science 312, 534-535
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882