Department of Molecular Biophysics & Physiology

The properties and biological functions of ion channels are long-term interests of Tom DeCoursey's laboratory. A major focus in recent years is the voltage-gated proton channel {Table}. Modulation of the voltage-dependence of this channel by pHo and pHi ensures that it opens only when the electrochemical gradient for H+ is outward (in most species). In other words, when the proton channel opens, it extrudes acid from cells. In a long collaboration with Dr. Vladimir V. Cherny and others, tThe Ganghe behavior of proton channels has been explored in alveolar epithelial cells and in white blood cells (human neutrophils and eosinophils). Immune cells engulf (phagocytose) bacteria and kill parasites by secreting reactive oxygen species (e.g., ChloroxTM). The enzyme responsible for these heroic actions is NADPH oxidase.  This enzyme moves electrons across the cell membrane to form superoxide anion near the invading critters. We measure the electron movement directly as an electrical current. For each electron that leaves, one proton stays in the cell. To prevent massive depolarization as well as acidification, protons exit the cell through proton channels.  Without H+ efflux, the killing process would be interrupted prematurely. Fortunately, proton channels are activated, relieving the cell of excess acid {Respiratory Burst figure; cartoon modified to show stoichiometry}, and preventing depolarization. The discovery of proton channels has been a great boon to cells, who until this time had to use other, less efficient means of extruding acid.
    Identification of proton channel genes in 2006 has transformed the field.  More functions are described each year, and structure-function studies are appearing.  The channel was shown to be a dimer, with conduction pathway in each protomer.  The dimer gates cooperatively - both protomers need to move before either conducts. New genes (eight confirmed, dozens speculated) are appearing at a high rate.  The proton channel resists efforts to crystallize it. The first
crystal structure was reported in 2014 by Takeshita et al, is likely closed, and is of a chimera with a Voltage-Sensing Phosphatase. James Letts' valiant efforts to determine the open structure of HV1 (a chimera with KVAP) can be found in his PhD dissertation, which also nicely shows that Asp112 mutants have severely compromised H+ flux!
HV1 triggers the flash in bioluminescent dinoflagellates (Smith et al, 2011), which were recently active in Tasmania

Quick summaries of proton channel lore:

{NSF summary of first dinoflagellate proton channel gene}

{Invited SciTopics entry on proton channels}

{Wikipedia entry on voltage-gated proton channels}

{Summary of recent Hv1 studies with special reference to phagocytes, by Boris Musset, in German!}

Susan M.E. Smith produced this phylogenetic tree showing known and predicted proton channels.  The length of each branch indicates the degree of difference from its neighbors.Phylogenetic tree

Other Items of Interest: Recent International Conferences 

Telluride Workshop on Proton Transfer in Biology, July, 2012


40 Years of Ion Channels:  A Marriage of Convenience
An Homage to Ramón Latorre, Centro Interdisciplinario de Neurosciencia de Valparaiso, Chile, October, 2011.
{video from award ceremony}


Telluride Scientific Research Conference on Proton Transfer in Biology, August, 2010

Bob Gennis' photo album

Gordon Conference on NOX Family NADPH Oxidases in Les Diablerets, Switzerland, June, 2010
P I C T U R E S - O F
C O N F E R E E S - A N D - S C E N E R Y

The Dr. Zhivago Biophysical Society meeting in Boston also in February 2009!

The Protons and Membrane Reactions Gordon Conference in Sunny, Pleasant Ventura California, February 2009

Telluride Workshop on Proton Transport and Solvation in Biology and Models Systems, August, 2007

 T   E   L   L   U   R   I   D   E   PIX

Sokendai International Symposium: Electrochemical Signalling by Membrane Proteins:  Biodiversity and Principle.
Okazaki Conference Center, National Institutes of Natural Sciences at Okazaki in Aichi Prefecture, Japan
, March, 2007
  trying  to  sit  on  the  floor  during  banquets

Gordon Conference on NOX Family NADPH Oxidases in Les Diablerets, Switzerland, October 15-20, 2006
P I C T U R E S - O F
A - T R I P - T O - A - G L A C I E R - T H E - A R E A - & - C O N F E R E E S

Group photo [1.9 Mbytes!] of the PHAGOCYTE WORKSHOP at the European Society for Clinical Investigation meeting in Praha, Czech Republic, March, 2006

Proton Solvation and Transport in Chemistry, Biology, and Materials Science: 200 Years After Grotthuss
a workshop sponsored by the Office of Basic Energy Sciences of the United States Department of Energy (DOE), June 25-28, 2006 in Washington, DC

"Proton Conduction in Diverse Media" a conference held at Fitzwilliam College, Cambridge, UK, April, 2005

Visiting David Colquhoun & Family (Andrew & Margaret) (600 kB) to give a seminar at University College London, April, 2005.

Check out David's web page - for a real treat, see his "Politics" page!
For Sports fans, see Andrew Colquhoun's web site - CRICKET!

Telluride Proton Channel Conference, August, 2004
A few pix: a  b  c  d  e  f  g  l  m  (I apologize to those not pictured - my camera did not take always take a picture when I pressed the button).
What's that spell???  (thanks to Noam Agmon)

Photos from the Nobel Symposium on Membrane Proteins: Structure, Function, and Assembly, Stockholm, Sweden. August 22-24, 2003.  Congratulations to Peter Agre and Rod MacKinnon!
(Thanks to Bob Gennis and Gunnar von Heijne for the photos!)

Photos from Moscow, June, 2002: International Conference on Membrane Bioelectrochemistry
in honor of Yuri Chizmadzhev, Frumkin Institute of Electrochemistry Mirsky, Ermakov, 3-Ds, Sokolov, Revelers, Feasters,Kremlin, RedSquare

Symposium on cardiac and skeletal electrophysiology:
A tribute to Professor Otto F. Hutter
Glasgow University, Scotland, May, 2002

Photos from the First International Proton Channel Conference in Villars, Switzerland, September, 2001! 
Lydia Henderson and Tom DeCoursey calmly discussing whether gp91phox is a proton channel - photo courtesy of Mel Okamura, four participants engrossed in discussion (Hu Xiao Wen, Lydia Henderson, Tom DeCoursey, and Erzebet Ligeti -photo courtesy of Roger C. Thomas), participants exhibiting single-minded purpose (l-r, back row: R.D. Vaughan-Jones, R.W. Meech, A. Maturana, K.H. Krause, B. Banfi (hidden), L.A. Pinto, l-r, front row: T.A. Cross, G. Bueldt, N. Demaurex), a typical meal, the group at Chillon Castle, at the H.R. Giger museum in Gruyeres, Larry and Maria Pinto y mi esposa Carolyn trying to fit into a Swiss car}

The Lab, Colleagues and Environs
M e l a n i a Capasso visited in M a y, 2011.  Susan M.E. Smith has generated useful homology models of the proton channel molecule based on its resemblance to the VSD (voltage sensing domain) of K+ channels.  Boris Musset from Marburg is our latest addition.  Deri Morgan, Ph.D. joined the lab in 2001. Claudia Eder visited in spring, 2002 (Claudia is below, Sue is above).
Here is the invaluable Tatiana Iastrebova in situ advising Dr. Cherny on electrode manufacturing techniques and in a less formal setting.
Former summer student researcherAudrey DeCoursey, now in Portland.  Audrey's avocation is entering beauty pageants (aka scholarship contests).  She was an actual Miss Portland contestant, and won the Mrs. Portland Mercury 2003 title, in part for her her talent "Demystifying the Citric Acid Cycle" performed with backup dancers  Bumpie and Pumpie who reenacted the reactions.  Here is our other daughter, Jillian.
Fellow advocates of phagocytes are Larry Thomas, Wei Xu, and Julie Murphy & Neeta Shenoy.
Bonus coverage:  a view of Seattle by bicycle (Mark S. Shapiro, Ph.D., tour-guide, now a Texan).
Life in the Department of Molecular Biophysics and Physiology would be impossible without Glenda Keaton-Mahone, Lucille Vaughn, and Ardessa Perkins.
Here is Tom expounding on the PROTON using a classical Pauling-esque marshmallow diagram (courtesy of daughter Jillian when in formative years).
Tom's c.v. (PDF)

Resources for Protonophiles
Antony Crofts has a nice discussion of proton conduction
Wolfgang Junge has some cool animations of the proton ATP synthase
Here is a useful nomogram showing the half-life of the superoxide anion before spontaneous disproportionation
(courtesy of Ricardo Murphy)
The Ukraine has a stamp showing the PROTON rocket.

Listen to Chris Hartzell's Chloride Channel Song!

Dante's Divine Comedy

United States Constitution (a little-known document these days)
To see a European view of American "ethics" check out David Colquhoun's awesome web site!

Selected Recent Publications

(OK, OK - ALL recent publications!)
Some PDF files require an online subscription to the journal. 
I am always happy to send reprints or PDFs.

Thomas, S., V.V. Cherny, D. Morgan, L.R. Artininan, V. Rehder, S.M.E. Smith, and T.E. DeCoursey.  2018.  Exotic properties of a voltage-gated proton channel in the snail Helisoma trivolvis.  Journal of General Physiology.  150:000-000. {PubMed}
{The very first proton currents were recorded in snail neurons by Roger Thomas and Bob Meech in 1982.
Here we identify a snail HVCN1 gene. When mammalian proton currents were seen in 1991, the most obvious difference was that they opened 3 orders of magnitude slower. Part of this difference is due to a "throttle" His at the inner end of the S3 helix. The most remarkable property of the Helisoma proton channel is that it responds very weakly to pHi, in contrast with all previously identified HV1.}

Cherny, V.V., D. Morgan, S. Thomas, S.M.E. Smith, and T.E. DeCoursey.  2018.  Histidine168 is crucial to ΔpH dependent gating of the human voltage gated proton channel, hHV1. Journal of General Physiology.  150:000-000. {PubMed}
ΔΔpH dependent gating of all proton channels is crucial to their functions. Discovered by Cherny et al, 1995 (below), changes in pHo or pHi shift the gH-V curve by 40 mV/unit.  Serendipitously, we discovered that mutations to His168 at the inner end of the S3 helix greatly attenuate the response to pHi, turning the human channel into snail.}

new DeCoursey, T.E.  (2018).  Voltage and pH sensing by the voltage gated proton channel, HV1.  Journal of the Royal Society Interface.  15: 20180198.  {pdf}
{I review current knowledge of voltage and pH sensing.  I propose a "counter-charge" model for pH sensing.}

Rodriguez, J.D., S. Haq, T. Bachvaroff, K.F. Nowak, S.J. Nowak, D. Morgan, V.V. Cherny, M.M. Sapp, S. Bernstein, A. Bolt, T.E. DeCoursey, A.R. Place, and S.M.E. Smith.  (2017).  Identification of a vacuolar proton channel that triggers the bioluminescent flash in dinoflagellates.  PLoS ONE.  12:e0171594.
{We report the discovery of a bona fide proton channel in a bioluminescent species of dinoflagellate - the same species Woody Hastings studied in his pioneering work that led to his being the first person to propose the existence of a voltage-gated proton channel.} 

DeCoursey, T.E.  (2015).  Structural revelations of the human voltage-gated proton channel.  Proceedings of the National Academy of Sciences, U.S.A. [Invited Commentary In press] {pdf}
{I discuss an EPR study of the human proton channel by Li et al (2015) PNAS.  They propose that hHV1 opens by the S4 helix moving up "one-click." Most folks thought that all three Arg in the hHV1 S4 segment moved from internally-accessible to externally-accessible during channel opening.  The new one-click model is consistent with our finding (Kulleperuma et al, 2013) that the third S4 Arg - R211H remains accessible to internal Zn2+ even in the open state.}

coverV.V. Cherny, D. Morgan, B. Musset, G. Chaves, S.M.E. Smith, and T.E. DeCoursey.  (2015).  Tryptophan 207 is crucial to the unique properties of the human voltage gated proton channel, hHV1.  Journal of General Physiology.  146:343-356. {PubMed, pdf}

{In the “signature sequence” that defines voltage gated proton channels is a perfectly conserved tryptophan adjacent to the second Arg in the S4 transmembrane helix: RxWRxxR.  Replacing Trp207 in hHV1 with Ala, Ser, or Phe accelerated channel opening by 100-fold, and closing by 30-fold.  Mutant channels opened at more negative voltages than WT, thus in WT channels Trp favors a closed state.  The Ea for channel opening decreased to 22 kcal/mol from 30-38 kcal/mol for WT;   Trp207 establishes the major energy barrier between closed and open hHV1.  Cation-π interaction between Trp207 and Arg211 latches the channel closed.  Trp207 mutants lost proton selectivity at pHo > 8.0.  Finally, ΔpH dependent gating, a universal feature of HV1 that is essential to its biological functions, was compromised.  Trp enables four characteristic properties: slow channel opening, highly temperature dependent gating kinetics, proton selectivity, and ΔpH dependent gating.

DeCoursey, T.E.  (2015).  The voltage-gated proton channel: a riddle, wrapped in a mystery, inside an enigma.  Biochemistry.  54:3250-3268. {pdf}
{This review updates unique properties of HV1 with a target audience of non-electrophysiologists.}

Dudev, T., B. Musset, D. Morgan, V.V. Cherny, S.M.E. Smith, K. Mazmanian, T.E. DeCoursey, and C. Lim.  (2015).  Selectivity mechanism of the voltage-gated proton channel, HV1.  Scientific Reports.  5:10320.  {pdf}
{Mutations and MD (molecular dynamics) identified the requirements for proton selectivity of HV1, but could not answer the 2-decade-old question:  Does proton selective conduction require protonation/deprotonation of the channel protein, or does it occur via a constrained water-wire?  We answer this question by using quantum calculations that include protonation chemistry.  The "salt bridge" between Asp112 (in human HV1) and Arg208 occludes the pore with two H bonds.  When H3O+ approaches, it breaks these bonds, protonates Asp, and forms a complex AspH0-H2O-Arg+ which can then protonate H2O to complete the cycle.  Other ions are excluded.}

Hondares, E., M.A. Brown, B. Musset, D. Morgan, V.V. Cherny, C. Taubert, M.K. Bhamrah, D. Coe, F. Marelli-Berg, J.G. Gribben, M.J.S. Dyer, T.E. DeCoursey, and M. Capasso.  (2014).  Enhanced activation of an amino-terminally truncated isoform of the voltage-gated proton channel HVCN1 enriched in malignant B cells.  Proceedings of the National Academy of Sciences, U.S.A.  111:18078-18083.  {pdf}
{We find that human B lymphocytes express two isoforms of the voltage-gated proton channel, HVCN1 - the full-length 273 amino acid Long form, and a Short form lacking the first 20 amino acids.  Short form channels respond more strongly to phosphorylation ("enhanced gating").  Normal B cells have mainly Long form, but B cells from 76 Chronic Lymphocytic Leukemia patients had high levels of Short form.  Short form interacted weakly with the B cell Receptor (BCR), hence was internalized less upon BCR activation.  The properties of Short form suggest that a contribution to the pathology of CLL and other B cell malignancies.}
DeCoursey, T.E., and J. Hosler
.  (2014).  Philosophy of voltage-gated proton channels.  Journal of the Royal Society Interface.  11: 20130799.  {pdf}
{This review discusses selected unique properties of HV1 from a teleological perspective.  Why does it need to be so selective?  Why bother to dimerize?  etc.}
Morgan, D., B. Musset, K. Kulleperuma, S.M.E. Smith, S. Rajan, V.V. Cherny, R. Pomčs, T.E. DeCoursey.  (2013).  Peregrination of the selectivity filter delineates the pore of the human voltage gated proton channel hHV1.  Journal of General Physiology.  142:625-640.  {pdf
{We move the selectivity filter Asp112 of hHV1 up and down the S1 transmembrane segment.  Three positions allow current, 109, 112 (WT) and 116; all face the pore in our model (Kulleperuma et al, 2013).  Asp109 (D112A/V109D) permits anion current, but does not enforce H+ selectivity.  Asp116 (D112V/V116D) produces excellent proton currents. MD indicates that proton selectivity requires that Asp (or Glu) interact with Arg to neutralize its charge.}
Here is the Video Summary

Smith, S.M.E. and T.E. DeCoursey, (2013).  Consequences of Dimerization of the Voltage-Gated Proton Channel. Ch. 12 in Oligomerization in Health and Disease. Eds, Jesús  Giraldo and Francisco Ceruela. Progress in Molecular Biology and Translational Science, Vol. 117, pp. 335-360.  UK: Academic Press.  {please email requests for the pdf}
{We describe the properties of dimeric and monomeric forms of HV1 and discuss the mystery of why the mammalian channel exists as a dimer.}

DeCoursey, T.E.  (2013).  Science and economy: Don't judge research on economics alone.  Commentary in Nature 497:40. {pdf}
{This is a response to a silly column proposing that research should be judged by its contribution to the economy.  There is ample evidence that research does contribute in a major way to our economy, and that money invested in research and education provides far more jobs than money invested in the military.  Furthermore, biomedical research cures disease and prolongs life.  That is worth more than money!]  

DeCoursey, T.E.  (2013).  Voltage-gated proton channels:  Molecular biology, physiology and pathophysiology of the HV family.  Physiological Reviews.  93:559-652. {pdf}
{Ten Years After!  Let's see - now the proton channel has genes!  The protein was a huge surprise - a self-standing VSD with strong similarities to, but also dramatic differences from the VSDs of other voltage-gated ion channels.  The list of cells and species continues to grow, along with an expanding diversity of functions.  Some
controversies persist, but their subject has changed.}

Kulleperuma, K., S.M.E. Smith, D. Morgan, B. Musset, J. Holyoake, N. Chakrabarti, V.V. Cherny, T.E. DeCoursey, and Régis Pomčs.  (2013).  Construction and validation of a homology model of the human voltage-gated proton channel hHV1.  Journal of General Physiology.  141:445-465. {pdf}
{We evaluate two open-state models of hHV1, using extensive molecular dynamics simulations and experiment.  Both approaches lead to a model with an open-state salt bridge between Asp112 and Arg208.  The first Arg partakes in an external charge cluster; the third in an internal cluster.  If proton channels were content to mimic other voltage-gated channels, they might move all three S4 Arg residues from internal to external vestibules.  But instead they opt for a stable open state!}

Musset, B., R.A. Clark, T.E. DeCoursey, G.L. Petheo, M. Geiszt, Y. Chen, J.E. Cornell, C.A. Eddy, R.G. Brzyski, and A. El Jamali.  (2012).  NOX5 in human spermatozoa: Expression, function and regulation.  Journal of Biological Chemistry.  287:9376-9388. {pdf}
{NOX5 is the main form of NADPH oxidase in human sperm, proton channels help regulate ROS production, and ROS production contributes to sperm motility.}

Musset, B., V.V. Cherny, and T.E. DeCoursey.  (2012).  Strong glucose dependence of electron current in human monocytes.  American Journal of Physiology: Cell Physiology.  302:C286-C295. {pdf}
{Human monocytes have proton channels and NADPH oxidase like other phagocytes.  PMA stimulation produces enhanced gating of HV1 and electron currents, which are small, but are quite sensitive to glucose concentration.}

DeCoursey, T.E.  (2012).  Voltage-gated proton channels.  Comprehensive Physiology.  2:1355-1385. {pdf}

Musset, B., and T.E. DeCoursey.  (2012).  Biophysical properties of the voltage gated proton channel HV1.  WIREs Membrane Transport and Signaling.  1:605–620. {pdf}
{Up-to-date reviews}

Musset, B., S.M.E. Smith, S. Rajan, D. Morgan, V.V. Cherny, and T.E. DeCoursey.  (2011) Aspartate112 is the selectivity filter of the human voltage gated proton channel.  Nature.  480:273-277.  {pdf}
{By swapping key residues from C15orf27, a molecule that is NOT a proton channel, into the human proton channel hHv1, we identify Asp112 in the middle of the S1 domain as the selectivity filter.  Surprisingly, most mutants are anion selective!  Only D112E remains proton specific.  Even more astoundingly, D112H conducts Cl-!  Mutant channels appear to be permeable to OH-.}

Smith, S.M.E., D. Morgan, B. Musset, V.V. Cherny, A.R. Place, J.W. Hastings, and T.E. DeCoursey. (2011). Voltage-gated proton channel in a dinoflagellate.  Proceedings of the National Academy of Sciences, U.S.A. 108:18162-18167.  {pdf}
{In 1972, Woody Hastings became the first human being to propose the existence of voltage-gated proton channels.  He postulated that they trigger the light flash produced by bioluminescent dinoflagellates.  Here we describe the first proton channel gene from a dinoflagellate, and show that its properties (heterologously expressed) are precisely what is required for this function.  Most notably, and in contrast to all other proton channels, these open well negative to the Nernst potential for protons.  Hence they conduct inward current.  Regenerative proton influx would produce action potentials as well as mediating the proton flux from vacuole into scintillon that triggers the flash.}

NSF coverage     German Version in

Cover Art Capasso, M., T.E. DeCoursey, and M.J.S. Dyer.  (2011).  pH regulation and beyond: unanticipated functions for the voltage gated proton channel, HVCN1.  Trends in Cell Biology.  21:20-28.  {pdf}
{We review novel functions of proton channels, focusing on recent developments.  By the way, the picture on the cover is the English (Proton) Channel.  First we included water and protons in the Channel, but then questions arose whether there should be a continuous row of waters or a titratable group, etc., so we left it unadorned as Nature intended.}

Musset, B., S.M.E. Smith, S. Rajan, V.V. Cherny, D. Morgan, and T.E. DeCoursey.  (2010).  Oligomerization of the voltage gated proton channel.  Channels.  4:260-265.  {pdf}
{In an Addendum to the Zn
2+ paper below, we propose that the main function of the C terminus is to tether the two protomers together, because the tandem WT dimer is very similar to the WT channel.}

Musset, B., S.M.E. Smith, S. Rajan, V.V. Cherny, S. Sujai, D. Morgan, and T.E. DeCoursey.  (2010).  Zinc inhibition of monomeric and dimeric proton channels suggests cooperative gating.  Journal of Physiology.  588:1435-1449.  {pdf}
{We compare the properties of monomeric vs. dimeric proton channels.  Zn2+ was thought to inhibit proton currents by binding competitively with protons at 2 His residues (Cherny & DeCoursey, 1999).  In the earliest model of a monomer, the two His are too far apart.  Here we find evidence that Zn2+ is coordinated between His at the interface between monomers. Recently the crystal structure of mHV1 has a Zn bound within a monomer (Takeshita et al, 2014).  Either the model was wrong, or the open-state model differs from the closed-state structure.}

Capasso, M., M.K. Bhamrah, T. Henley, R.S. Boyd, C. Langlais, K. Cain, D. Dinsdale, K. Pulford, M. Khan, B. Musset, V.V. Cherny, D. Morgan, R.D. Gascoyne, E. Vigorito, T.E. DeCoursey, I.C.M. MacLennan, and M.J.S. Dyer.  (2010).  HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species.  Nature Immunology.  11:265-272.   {pdf}
{A cast of thousands was needed to describe the multiple functions of proton channels in human B lymphocytes!}

Musset, B., M. Capasso, V.V. Cherny, D. Morgan, M. Bhamrah, M.J.S. Dyer, and T.E. DeCoursey.  (2010).  Identification of Thr29 as a critical phosphorylation site that activates the human proton channel Hvcn1 in leukocytes.  Journal of Biological Chemistry.  285:5117-5121.   {pdf}
{We identify Thr29 as the main phosphorylation site on the proton channel.  Phosphorylating this site on the intracellular N terminus appears to convert the channel into the "enhanced gating mode."}

DeCoursey, T.E.  (2010).  Voltage-gated proton channels find their dream job managing the respiratory burst in phagocytes.  Physiology.  25:27-40.  {pdf}
{The latest proton channel lore is updated, with a focus on the role in the phagocyte respiratory burst.  New cartoons!}

Morgan, D., M. Capasso, B. Musset, V.V. Cherny, E. Ríos, M.J.S. Dyer, T.E. DeCoursey. (2009). Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis.  Proceedings of the National Academy of Sciences, U.S.A.  106:18022-18027.  {pdf}
{We examine cytoplasmic pH of human neutrophils during phagocytosis using confocal imaging, SNARF-1, and SEER.  Convention says Na
/H antiport is the main pH regulator, but we find proton channels are also required.  In fact, proton channels respond first! In HVCN1 KO mice, pHi drops during phagocytosis as much as with Zn2+, showing that the effects of Zn2+ are mainly due to inhibiting proton channels.}
DeCoursey, T.E. (2009) Unintended consequences at NIH.  Science. Jan 9;323(5911):209.
 {I say what everyone is thinking - squandering NIH funds on project grants and other boondoggles, together with the obscenely low funding rate of R01 applications threatens to cripple basic biomedical research in the United States.  Please send your suggestions to the Obama Administration!  Their intentions are good.  They must be made to recognize that the R01 payline is the fundamental criterion for the viability of research - our present course is not sustainable and will produce disastrous consequences that have already begun.  The beneficial effects on the economy of a stimulus directed at biomedical research are clear and this is the enlightened direction we want for our country.}

Musset, B., V.V. Cherny, D. Morgan, and T.E. DeCoursey.  (2009).  The intimate and mysterious relationship between proton channels and NADPH oxidase.  FEBS Letters.  583:7-12. {pdf}
 {The title says it all!  We describe the inexplicable interactions between proton channels and NADPH oxidase, and discuss several kinds of mechanisms that might explain them.}

DeCoursey, T.E.  (2008).  Voltage-gated proton channels: What’s next?  Journal of Physiology.  586:5305-5324.  {Topical Review}

 {I list the major questions that remain;  there seem to be more questions than answers.  This means proton channels will continue to entertain us for years!}

DeCoursey, T.E.  (2008).  Voltage-gated proton channels.  Cellular and Molecular Life Sciences.  65:2554-2573.  {pdf}
 {This brings the history of proton channels up to date.}

Musset, B., D. Morgan, V.V. Cherny, D.W. MacGlashan, Jr., L.L. Thomas, E. Ríos, and T.E. DeCoursey.  (2008).  A pH-stabilizing role of voltage gated proton channels in IgE-mediated activation of human basophils.  Proceedings of the National Academy of Sciences, U.S.A.  105:11020-11025.  {pdf}
{Proton channels in human basophils exhibit enhanced gating when stimulated with secretagogues, PMA or anti-IgE.  Inhibition of histamine release by Zn2+ suggests a role for proton channel activity.  This idea is supported by demonstration that Zn2+ also enhances the cytoplasmic acidification that occurs upon stimulation with anti-IgE.}

Musset, B., V.V. Cherny, D. Morgan, Y. Okamura, I.S. Ramsey, D.E. Clapham, and T.E. DeCoursey.  (2008).  Detailed comparison of expressed and native voltage-gated proton channel currents.  Journal of Physiology.  586:2477-2486.  {pdf}   Read Claudia Eder's commentary!
{We express the recently-identified human and mouse proton channel genes in HEK-293 or COS-7 cells.  Although in nearly every respect, the currents resemble native proton currents, one difference is noted: the voltage dependence is shifted by about -30 mV.  As a result, inward currents can be seen, even at symmetrical pH, something never observed in any native cell.  We rule out various explanations, but do not discover the reason for this anomaly.}

DeCoursey, T.E., and V.V. Cherny.  (2007).  Pharmacology of voltage-gated proton channels.  Current Pharmaceutical Design. 13:2406-2420.  {journal link}
{We review the pharmacology of proton channels;  in a word, Zinc!}

DeCoursey, T.E.  (2007).  Electrophysiology of the phagocyte respiratory burst.  Focus on "Large-conductance calcium-activated potassium channel activity is absent in human and mouse neutrophils and is not required for innate immunity" American Journal of Physiology: Cell Physiology. 293:C30-C32.  {pdf}
{This provides the context for the study:  Essin, K., B. Salanova, R. Kettritz, M. Sausbier, F.C. Luft, D. Kraus, E. Bohn, I.B. Autenrieth, A. Peschel, P. Ruth, and M. Gollasch.  (2007).  Large-conductance calcium-activated potassium channel activity is absent in human and mouse neutrophils and is not required for innate immunity. Am J Physiol Cell Physiol 293 C45-C54.  Essin and colleagues thoroughly evaluate the "BK hypothesis" of Ahluwalia et al (2004) and find no evidence to support it.  Among new tests not done by Femling et al (2006) below, they used BK channel KO mice, and found their neutrophils normal in every respect, with no evidence for BK channel expression or function. Another study that further disproves the BK hypothesis by Essin et al has also appeared.}

Morgan, D., V.V. Cherny, A. Finnegan, J. Bollinger, M.H. Gelb, and T.E. DeCoursey.  (2007).  Sustained activation of proton channels and NADPH oxidase in human eosinophils and murine granulocytes requires PKC but not cPLA2a activity.  Journal of Physiology.  579:327-344. {pdf}.

 {We test and discard the prevailing hypothesis that proton channels are activated by arachidonic acid (AA) produced by cPLA2a. Specific blockers have no effect, nor is the response changed in knockout mice.  However, PKC inhibitors prevent activation of NADPH oxidase and H channels, and can reverse their activation.  Most surprisingly, part of the effect of AA is sensitive to PKC inhibitors; hence AA activates PKC, not vice versa!}

DeCoursey, T.E.  (2006).  The pros and cons of open peer review. Should authors be told who their reviewers are?  Nature  {Invited online commentary.  Posted 14 June, 2006} 
 {Perhaps manuscript reviewers' identities should be printed when a paper is published, to increase the accountability of reviewers.}

Femling, J.K., V.V. Cherny, D. Morgan, B. Rada, A.P. Davis, G. Czirják, P. Enyedi, S.K. England, J.G. Moreland, E. Ligeti, W.M. Nauseef, and T.E. DeCoursey. (2006).  The antibacterial activity of human neutrophils and eosinophils requires proton channels but not BK channels. Journal of General Physiology. 127:659-672. {pdf}
{In a full investigation of the topic raised in the Science STKE Perspective below, we cannot reproduce any of the main conclusions of Ahluwalia et al, 2004 (Nature 427:853-858).  There are no BK currents, nor is the BK protein expressed in human neutrophils. BK inhibitors have no effect on currents nor any functional behavior of neutrophils or eosinophils. IbTX has no effect on the ability of neutrophils to kill bacteria.   However, H2O2 measurements reaffirm that proton channels are necessary for sustained NADPH oxidase activity.  Achtung!The Ahluwalia paper has now been retracted!}
Murphy, R., and T.E. DeCoursey.  (2006).  Charge compensation in phagocytes. Biochimica et Biophysica Acta. 1757:996-1011.
{After saying for years "charge compensation by proton channels is necessary to keep the electrogenic NADPH oxidase working," we realize that in addition to compensating charge  (to balance the electron flux) proton flux performs several additional necessary functions during the respiratory burst:  (1) it prevents large pH excursions in the cell and phagosome, (2) it minimizes osmotic consequences, and (3) protons are necessary substrates to produce reactive oxygen species.  Thus, even if charge compensation were not necessary, proton flux would still be required.  A mathematical model shows that other conductances can contribute at most ~5% to charge compensation in human neutrophils and eosinophils.}

DeCoursey, T.E.  (2006).  It’s difficult to publish contradictory findings.  Nature.  439:784.
 {I gripe about the difficulty in publishing "negative" or "contradictory" results, despite their obvious importance to scientific progress.}

Morgan, D., V.V. Cherny, R. Murphy, B.Z. Katz, and T.E. DeCoursey.  (2005).  The pH dependence of NADPH oxidase in human eosinophils.  Journal of Physiology.  569:419-431. {pdf}.
{NADPH oxidase is strongly inhibited above or below pHi 7.5, but is not affected by pHo.  Surprisingly, electron current in inside-out patches (reflecting the turnover of the enzyme per se) is only weakly sensitive to pHi.  Evidently a step in assembly or deactivation of the NADPH oxidase complex accounts for the pH sensitivity in intact cells.}

DeCoursey, T.E., and E. Ligeti.  (2005).  Regulation and termination of NADPH oxidase activity.  Cellular and Molecular Life Sciences. 62:2173-2193. {Review}
 {We exami
ne the question of what turns off NADPH oxidase after the respiratory burst, and discover that we do not know the answer.}

Murphy, R., V.V. Cherny, D. Morgan, and T.E. DeCoursey.  (2005).  Voltage-gated proton channels help regulate pHi in rat alveolar epithelium.  American Journal of Physiology - Lung Cellular and Molecular Physiology.  288:L398-L408. {pdf}
{Proton channels help restore pHi after acid loading alveolar epithelial cells.  This is the first demonstrated function for proton channels in the mammalian cells first found to express proton channels (1991)}

DeCoursey, T.E.  (2004).  During the respiratory burst, do phagocytes need proton channels or potassium channels or both? Science's STKE.  2004: pe21. {Perspective on Ion Channels in Phagocytes-pdf}.
{This Perspective critiques a recent paper by the Segal group (Ahluwalia et al, 2004. Nature 427:853-858) which reports that maxi-K channels are the only ion channels in PMA-activated neutrophils and eosinophils, and hence perform all channel-mediated tasks.  Other labs (including ours) do not see these currents, but see proton currents instead.  K+ flux may serve a useful function, but we feel that proton efflux is the main charge compensation mechanism.}

DeCoursey, T.E.  (2003).  Interactions between NADPH oxidase and voltage-gated proton channels: Why electron transport depends on proton transport. FEBS Letters. 555:57-61.  {Summary, Full text + links, pdf}.
 {The physiological interaction between NADPH oxidase and voltage-gated proton channels in phagocytes is reviewed.  A putative electron pathway through NADPH oxidase is discussed, and speculations about the rate-limiting steps at different voltages are presented.}
Cherny, V.V., R. Murphy, V. Sokolov, R.A. Levis, and T.E. DeCoursey.  (2003).  Properties of single voltage-gated proton channels in human eosinophils estimated by noise analysis and direct measurement.  Journal of General Physiology.  121:615-628. {Abstract, FullText, pdf}
 {We determine the conductance of a single proton channel.  We claim the world's smallest directly-measured single-channel currents (7-16 fA).  Noise analysis provides more surprises!}
Morgan, D. V.V. Cherny, R. Murphy, W. Xu, L.L. Thomas, and T.E. DeCoursey.  (2003). Temperature dependence of NADPH oxidase in human eosinophils. Journal of Physiology. {Abstract, pdf}
{The temperature dependence of NADPH oxidase activity is determined.  The intrinsic Ea of electron flux is low (only 14 kcal/mol), but that of the steady-state enzyme activity is much greater (25 kcal/mol), evidently due to strongly temperature-sensitive assembly of the oxidase complex.  More NADPH oxidase complexes assemble at body temperature.}
DeCoursey, T.E., D. Morgan, and V.V. Cherny.  (2003).The voltage dependence of NADPH oxidase reveals why phagocytes need proton channels.  Nature.  422:531-534. {pdf}
 {The voltage dependence of NADPH oxidase activity (electron current) is determined.  Enzyme activity is abolished by extreme depolarization of the cell membrane.  Unexpectedly strong rectification of the electron current-voltage curve resolves the decade-long mystery of apparent discrepancies between the [Zn2+] that inhibits proton channels vs. that which inhibits NADPH oxidase activity (superoxide production). }

DeCoursey, T.E.  (2003). Voltage-gated Proton Channels and Other Proton Transfer Pathways. Physiological Reviews. 83:475-579.
(free pdf download, 2.1 mBytes, lots of color pix)
{Voltage-gated proton channels are reviewed, along with other proton-conducting molecules for comparison.
Valuable prizes will be awarded to those who can prove that they have read the entire review.}

Morgan, D., and T.E. DeCoursey.  (2003).  Diversity of voltage-gated proton channels.  Frontiers in Bioscience.  8:s1266-s1279.{abstract, pdf-requires subscription}
{An abridged version of the big review.  This is part of a special Proton Transport issue of this online journal.}

Schilling, T., A. Gratopp, T.E. DeCoursey, and C. Eder.  (2002).  Voltage-activated  proton currents in human lymphocytes. Journal of Physiology.  545:93-105. {Abstract, full text, pdf}
{More than 700 papers had been published on ion channels in lymphocytes before we finally showed that they have proton channels too!}

DeCoursey, T.E., D. Morgan, and V.V. Cherny.  (2002).  The gp91phox component of NADPH oxidase is not a voltage-gated proton channel. Journal of General Physiology.  120:773-779. {Abstract, full text, pdf}
{We summarize the arguments against the hypothesis that one component of NADPH oxidase functions as a proton channel.}

Morgan, D. V.V. Cherny, M.O. Price, M.C. Dinauer, and T.E. DeCoursey.  (2002).  Absence of proton channels in COS-7 cells expressing functional NADPH oxidase components. Journal of General Physiology. 119:571-580.  {pdf}
{This paper counters arguments raised against the paper listed next.  We show that cells that lack endogenous proton channels still lack them when transfected with gp91phox and other components of NADPH oxidase. Therefore, gp91phox is not a proton channel in phagocytes.}

DeCoursey, T.E., V.V. Cherny, D. Morgan, B.Z. Katz, M.C. Dinauer.  (2001). The gp91phox component of NADPH oxidase is not the voltage-gated proton channel in phagocytes, but it helps. Journal of Biological Chemistry. (Accelerated Publication) 276:36063-36066.
{Identical proton currents are found in control PLB-985 cells, gp91phox knock-outs (and re-transfectants) and in human CGD phagocytes that lack gp91phox expression.  Furthermore, stimulation with PMA increases the proton conductance identically in all cells.  Therefore, gp91phox is not a proton channel in phagocytes.}

DeCoursey, T.E., V.V. Cherny, A.G. DeCoursey, W. Xu and Thomas, L.L. (2001). Interactions between NADPH oxidase-related proton and electron currents in human eosinophils. Journal of Physiology.  535:767-781. {pdf}
{Human eosinophils are shown to have thrice larger electron currents than neutrophils, consistent with their higher rate of superoxide production.  We present evidence that there is a single type of proton channel before and after stimulation with PMA, and that the reported enhanced Zn2+ sensitivity of proton channels in activated cells is an artifact.}

Cherny, V.V., L.M. Henderson, W. Xu, L.L. Thomas and T.E. DeCoursey.  (2001).  Activation of NADPH oxidase-related proton and electron currents in human eosinophils by arachidonic acid.  Journal of Physiology. 535:783-794. {pdf}
{Arachidonic acid enhances proton channel gating similarly to PMA.  The data are mostly consistent with the proposal by Henderson et al (1993) that AA is the final step in the signaling pathways that activate both NADPH oxidase and proton channels.}

Cherny, V.V., L.L. Thomas and T.E. DeCoursey.  (2001).  Voltage-gated proton currents in human basophils.  Biologicheskie Membrany 6:458-465.
{Human basophils are found to have huge proton currents like eosinophils (which have the highest expression of any cell).  This result is surprising, because proton channels compensate for electron flux through NADPH oxidase , which is essentially absent in basophils.}

Eder, C., and T.E. DeCoursey.  (2001).  Voltage-gated proton channels in microglia.  Progress in Neurobiology. 64:277-305. {REVIEW}
{We review the properties of proton channels in all cells, but focus on special roles in microglia.}

Selected papers published in the previous millennium

Schilling T, Quandt FN, Cherny VV, Zhou W, Heinemann U, DeCoursey TE, Eder C (2000) Upregulation of Kv1.3 K+ channels in microglia deactivated by TGF-b. Am J Physiol Cell Physiol 279:C1123-C1134. {abstract, PDF}

DeCoursey, T.E., V.V. Cherny, W. Zhou, and L.L. Thomas.  (2000).  Simultaneous activation of NADPH oxidase-related proton and electron currents in human neutrophils.  Proceedings of the National Academy of Sciences, U.S.A. 97:6885-6889. {abstract, PDF}

DeCoursey, T.E., and V.V. Cherny.  (2000).  Common themes and problems of bioenergetics and voltage-gated proton channels. Biochimica Biophysica Acta 1458:104-119.{abstract, full text}

The following two papers are my MILLENIUM BOOKENDS:
  The LAST paper published in the LAST issue of The Journal of General Physiology in the 20th Century and the FIRST paper in the FIRST issue of the American Journal of Physiology: Cell Physiology in the 21st Century!

DeCoursey, T.E.  (2000).  Hypothesis: do voltage-gated H+ channels in alveolar epithelial cells contribute to CO2 elimination by the lung? Amer. J. Physiol. Cell Physiol. 278:C1-C10. {abstract, full-text, PDF} This figure {69 kb, taken from this paper, with permission} illustrates the hypothetical involvement of proton channels in extruding CO2.

Cherny, V.V., and T.E. DeCoursey.  (1999).  pH dependent inhibition of voltage-gated H+ currents in rat alveolar epithelial cells by Zn2+ and other divalent cations. J. Gen. Physiol. 114:819-838. {abstract, fulltext, PDF}

DeCoursey, T.E. and V.V. Cherny.  (1998).  Temperature dependence of voltage-gated H+ currents in human neutrophils, rat alveolar epithelial cells, and mammalian phagocytes.  J. Gen. Physiol. 112:503-522. {abstract//fulltext//PDF}

DeCoursey, T.E. (1998). Four varieties of voltage-gated proton channels. Frontiers in Bioscience. 3:d477-d482. {full-length review}

Captain Proton web site 
Zhou, W., F.S. Cayabyab, P.S. Pennefather, L.C. Schlichter and T.E. DeCoursey. (1998). HERG-like K+ channels in microglia. J. Gen. Physiol. 111:781-794. {abstract//fulltext//PDF}

Pennefather P.S., W. Zhou and T.E. DeCoursey. (1998). Idiosyncratic gating of HERG-like K+ channels in microglia. J. Gen. Physiol. 111:795-805. {abstract//fulltext/PDF}

DeCoursey, T.E. and V.V. Cherny. (1997). Deuterium isotope effects on permeation and gating of proton channels in rat alveolar epithelium. J. Gen. Physiol. 109:415-434. {abstract//fulltext//PDF}

DeCoursey, T.E., S.Y. Kim, M.R. Silver and F.N. Quandt. (1996). III. Ion channel expression in PMA-differentiated human THP-1 macrophages. J. Membrane Biol. 152:141-157. {abstract}

Cherny, V.V., V.S. Markin and T.E. DeCoursey. (1995). The voltage-activated hydrogen ion conductance in rat alveolar epithelial cells is determined by the pH gradient. J. Gen. Physiol. 105:861-896. {abstract}
DeCoursey, T.E. and V.V. Cherny.(1995).Voltage-activated proton currents in membrane patches of rat alveolar epithelial cells.J. Physiol.489:299-307. {abstract}

DeCoursey, T.E. and V.V. Cherny. (1994). Voltage-activated hydrogen ion currents. J Membrane Biol. 141:203-223. [review]

DeCoursey, T.E.  (1991).  Hydrogen ion currents in rat alveolar epithelial cells.  Biophysical Journal.  60:1243-1253. {First description of voltage-gated proton channels in mammalian cells}

Swift, J. (1729). A modest proposal{Swift's proposal is more relevant than ever!!}

Here is a cool time-lapse view of Chicago taken near Rush.


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