The Voltage-Gated Proton Channel: A Riddle, Wrapped in a Mystery, inside an Enigma

DeCoursey, Thomas E.

doi:10.1021/acs.biochem.5b00353

Cited by 48 publications

(50 citation statements)

References 231 publications

(665 reference statements)

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“…The voltage-gated proton channel, H V 1, is notoriously unique among ion channels (1), and plays key roles in the health and disease of diverse tissues and species (2). Li et al (3) combine biochemical, computational, and electron paramagnetic resonance (EPR) spectroscopic approaches to shed light on structural aspects of the human proton channel, hH V 1.…”

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confidence: 99%

Structural revelations of the human proton channel

DeCoursey

2015

Proc. Natl. Acad. Sci. U.S.A.

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The voltage-gated proton channel, H V 1, is notoriously unique among ion channels (1), and plays key roles in the health and disease of diverse tissues and species (2). Li et al. (3) combine biochemical, computational, and electron paramagnetic resonance (EPR) spectroscopic approaches to shed light on structural aspects of the human proton channel, hH V 1. Their results advance the field in several key areas, culminating in a bold new model for gating.The voltage-sensing domain (VSD) is the part of voltage-gated ion channels that senses the electrical potential across the cell membrane where the channel resides. Most such channels open upon membrane depolarization, which is accomplished mainly by cationic amino acids located in the fourth transmembrane helical segment (S4) moving outward when the inside of the cell is made more positive. This movement is transduced from the VSD (S1-S4) to the pore region (S5-S6), opening a conduction pathway. In addition to biologically important voltagegated K + , Na + , Ca 2+ , and H + channels, other classes of membrane proteins with VSDs exist that are not channels at all. One example is a voltage-sensing phosphatase (VSP), an enzyme whose activity is regulated by membrane potential. In a landmark study in 2014 (4), the Li-Perozo group reported crystal structures for CiVSP in both "down" and "up" conformations, the first VSD-containing molecule to have structures determined in both states. Voltage-gated ion channels are closed at negative voltages, and open upon depolarization as the S4 helix moves "up" through the membrane electrical field. Because the VSP is not a channel, "closed" and "open" become "down" and "up." The gene for hH V 1 was identified only in 2006 (5). To the astonishment of everyone, the gene product bore a striking resemblance to the VSD of other voltage-gated ion channels, so much so that the simultaneously identified mouse (mH V 1) and Ciona intestinalis (CiH V 1) gene products were dubbed VSOP or "voltage sensor-only protein" (6). H V 1 has only four membrane-spanning helices (S1-S4); these sense voltage but also contain the proton conduction pathway (7).Crystal structures are great, up to a point. They provide tremendously detailed information about molecules, but they have limitations that are sometimes overlooked. They tell us about structure, but only the structure of whatever exists in the crystal. Proteins have many conformations, and one must determine or guess which one was captured during crystallization, and hope it is a native conformation and not a broken one. Forming crystals of membrane proteins is challenging, and often the protein is modified to facilitate crystallization. Ligands or chaperone-like proteins are included, parts of the molecule are truncated, chimerae are produced: whatever it takes to get a good crystal. H V 1 has not been successfully crystallized in its entirety. First came crystal structures of the C terminus alone that lacked the entire transmembrane region (8, 9). Then in 2014, the first exciting glimpse of H V 1 ap...

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confidence: 99%

Structural revelations of the human proton channel

DeCoursey

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although there is no shortage of information about NHE-1 and its contribution to HF, there is no information concerning proton channels in the heart and whether these channels could be indirectly implicated with NHE-1 in the development of sodium overload leading to the development of HF and early death. This type of channel was reported to be mostly present in immune cells (DeCoursey 2012(DeCoursey , 2013(DeCoursey , 2015. As can be seen in Fig.…”

Section: Presence Of the Voltage-gated H ؉ Channel (Hv1) In Cardiovasmentioning

confidence: 79%

“…This intracellular acidosis concomitantly takes place with the early development of the intracellular sodium overload in heart cells of the DMD and BMD hereditary hamster model. Escaping intracellular acidosis is mainly taken care of by at least 2 major proton transporters, the NHE-1 and the voltage-gated H + channel (Hv1) (for more information about Hv1, please refer to DeCoursey 2012DeCoursey , 2013DeCoursey , 2015. Although there is no shortage of information about NHE-1 and its contribution to HF, there is no information concerning proton channels in the heart and whether these channels could be indirectly implicated with NHE-1 in the development of sodium overload leading to the development of HF and early death.…”

Section: Presence Of the Voltage-gated H ؉ Channel (Hv1) In Cardiovasmentioning

confidence: 99%

Na⁺–H⁺exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies

Bkaily

Jacques

2017

Can. J. Physiol. Pharmacol.

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Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (␦-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na + overload and early death due to HF. Our previous work also showed that another proton transporter, the voltage-gated proton channel (Hv1), exists in many cell types including heart cells and skeletal muscle fibers. The Hv1 could be indirectly implicated in the beneficial effect of blocking NHE-1.Key words: Becker muscular dystrophy, Duchenne muscular dystrophy, heart failure, NHE-1, proton channel. Résumé :On peut observer une cardiomyopathie chez des patients atteints de dystrophie musculaire de Duchenne (DMD) ou de Becker (DMB). Cette atteinte est liée à des maladies musculaires causées par des mutations dans le gène de la dystrophine. Les défauts dans la dystrophine sont présents dans la DMD, mais dans la DMB légère aussi. Le hamster de la souche UM-X7.1, atteint de cardiomyopathie héréditaire, constitue un modèle expérimental particulier d'insuffisance cardiaque (IC) menant à une mort précoce en cas de dystrophie musculaire (carence en dystrophine et mutation dans le gène de la sarcoglycane) et de maladie cardiaque (carence en ␦-sarcoglycane et mutation dans le gène de la dystrophine) chez des humains atteints de DMD. À l'aide de ce modèle, nos travaux précédents ont montré un défaut dans l'homéostasie du sodium intracellulaire avant l'apparition de tout défaut biochimique ou histologique apparent. Nous avons attribué ce phénomène à la présence continuelle de canaux sodiques lents foetaux, que l'on a aussi retrouvés sous une forme active dans la DMD chez l'humain. En raison de l'acidose intracellulaire musculaire, la surcharge intracellulaire de sodium dans la DMD et la DMB était aussi causée par le passage de sodium par l'échangeur sodium-hydrogène NHE-1. Le traitement à vie avec un inhibiteur du NHE-1 permettait de prévenir la surcharge intracellulaire de Na + et le décès précoce causé par l'IC. Nos travaux précédents ont aussi montré que le Hv1 (canal à protons dépendant du voltage), un autre transporteur de protons, existe dans de nombreux type...

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“…Similarly, Hv1-deficient rats lack a fatal/severe phenotype (Jin et al, 2014). The phenotypes of Hv1-deficient animal models cannot be directly extrapolated to the human scenario because of some differences regarding Hv1 expression among species (Lishko et al, 2010), and no human deficiency of Hv1 is known (DeCoursey, 2015). Nonetheless, these results suggest that the pharmacological inhibition of Hv1 channel could be feasible because of tolerable toxicity and potential relevant effect in both tumor cell biology and tumor-infiltrating immune cells.…”

Section: Perspectives Of the Pharmacological Inhibition Of Proton Chamentioning

confidence: 99%

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

et al. 2016

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The pharmacological modulation of the immunosuppressive tumor microenvironment has emerged as a relevant component for cancer therapy. Several approaches aiming to deplete innate and adaptive suppressive populations, to circumvent the impairment in antigen presentation, and to ultimately increase the frequency of activated tumor-specific T cells are currently being explored. In this review, we address the potentiality of targeting the voltage-gated proton channel, Hv1, as a novel strategy to modulate the tumor microenvironment. The function of Hv1 in immune cells such as macrophages, neutrophils, dendritic cells, and T cells has been associated with the maintenance of NADPH oxidase activity and the generation of reactive oxygen species, which are required for the host defense against pathogens. We discuss evidence suggesting that the Hv1 proton channel could also be important for the function of these cells within the tumor microenvironment. Furthermore, as summarized here, tumor cells express Hv1 as a primary mechanism to extrude the increased amount of protons generated metabolically, thus maintaining physiologic values for the intracellular pH. Therefore, because this channel might be relevant for both tumor cells and immune cells supporting tumor growth, the pharmacological inhibition of Hv1 could be an innovative approach for cancer therapy. With that focus, we analyzed the available compounds that inhibit Hv1, highlighted the need to develop better drugs suitable for patients, and commented on the future perspectives of targeting Hv1 in the context of cancer therapy.

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The Voltage-Gated Proton Channel: A Riddle, Wrapped in a Mystery, inside an Enigma

Cited by 48 publications

References 231 publications

Structural revelations of the human proton channel

Structural revelations of the human proton channel

Na⁺–H⁺exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

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The Voltage-Gated Proton Channel: A Riddle, Wrapped in a Mystery, inside an Enigma

Cited by 48 publications

References 231 publications

Structural revelations of the human proton channel

Structural revelations of the human proton channel

Na+–H+exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

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Na⁺–H⁺exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies