scholarly journals Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle?

2016 ◽  
Vol 310 (8) ◽  
pp. R679-R690 ◽  
Author(s):  
Paul M. O'Connor ◽  
Avirup Guha ◽  
Carly A. Stilphen ◽  
Jingping Sun ◽  
Chunhua Jin
Keyword(s):  
Experimental Studies ◽  
Proton Channel ◽  
Thick Ascending Limb ◽  
Phagocytic Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Medullary Thick Ascending Limb ◽  
Current Controversy ◽  
Experimental Approaches ◽  
Species Production

Hv1 is a voltage-gated proton channel highly expressed in phagocytic cells, where it participates in the NADPH oxidase-dependent respiratory burst. We have recently identified Hv1 as a novel renal channel, expressed in the renal medullary thick ascending limb that appears to importantly contribute to the pathogenesis of renal hypertensive injury in the Dahl salt-sensitive rat model. The purpose of this review is to describe the experimental approaches that we have undertaken to identify the source of excess reactive oxygen species production in the renal outer medulla of Dahl salt-sensitive rats and the resulting evidence that the voltage-gated proton channel Hv1 mediates augmented superoxide production and contributes to renal medullary oxidative stress and renal injury. In addition, we will attempt to point out areas of current controversy, as well as propose areas in which further experimental studies are likely to move the field forward. The content of the following review was presented as part of the Water and Electrolyte Homeostasis Section New Investigator Award talk at Experimental Biology 2014.

Voltage-gated proton channels help regulate pHi in rat alveolar epithelium

2005 ◽  
Vol 288 (2) ◽  
pp. L398-L408 ◽  
Author(s):  
Ricardo Murphy ◽  
Vladimir V. Cherny ◽  
Deri Morgan ◽  
Thomas E. DeCoursey
Keyword(s):  
Epithelial Cells ◽  
Ph Regulation ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Proton Channel ◽  
Resting Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Alveolar Epithelial

Voltage-gated proton channels are expressed highly in rat alveolar epithelial cells. Here we investigated whether these channels contribute to pH regulation. The intracellular pH (pHi) was monitored using BCECF in cultured alveolar epithelial cell monolayers and found to be 7.13 in nominally HCO3−-free solutions [at external pH (pHo) 7.4]. Cells were acid-loaded by the NH4+ prepulse technique, and the recovery was observed. Under conditions designed to eliminate the contribution of other transporters that alter pH, addition of 10 μM ZnCl2, a proton channel inhibitor, slowed recovery about twofold. In addition, the pHi minimum was lower, and the time to nadir was increased. Slowing of recovery by ZnCl2 was observed at pHo 7.4 and pHo 8.0 and in normal and high-K+ Ringer solutions. The observed rate of Zn2+-sensitive pHi recovery required activation of a small fraction of the available proton conductance. We conclude that proton channels contribute to pHi recovery after an acid load in rat alveolar epithelial cells. Addition of ZnCl2 had no effect on pHi in unchallenged cells, consistent with the expectation that proton channels are not open in resting cells. After inhibition of all known pH regulators, slow pHi recovery persisted, suggesting the existence of a yet-undefined acid extrusion mechanism in these cells.

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.

scholarly journals Regulation of Neutrophil Functions by Hv1/VSOP Voltage-Gated Proton Channels

2021 ◽  
Vol 22 (5) ◽  
pp. 2620
Author(s):  
Yoshifumi Okochi ◽  
Yasushi Okamura
Keyword(s):  
Hypochlorous Acid ◽  
Proton Channel ◽  
Ros Generation ◽  
Ros Production ◽  
Proton Extrusion ◽  
Charge Imbalance ◽  
Proton Channels ◽  
Extracellular Signal Regulated Kinase ◽  
Voltage Gated ◽  
Extracellular Signal

The voltage-gated proton channel, Hv1, also termed VSOP, was discovered in 2006. It has long been suggested that proton transport through voltage-gated proton channels regulate reactive oxygen species (ROS) production in phagocytes by counteracting the charge imbalance caused by the activation of NADPH oxidase. Discovery of Hv1/VSOP not only confirmed this process in phagocytes, but also led to the elucidation of novel functions in phagocytes. The compensation of charge by Hv1/VSOP sustains ROS production and is also crucial for promoting Ca2+ influx at the plasma membrane. In addition, proton extrusion into neutrophil phagosomes by Hv1/VSOP is necessary to maintain neutral phagosomal pH for the effective killing of bacteria. Contrary to the function of Hv1/VSOP as a positive regulator for ROS generation, it has been revealed that Hv1/VSOP also acts to inhibit ROS production in neutrophils. Hv1/VSOP inhibits hypochlorous acid production by regulating degranulation, leading to reduced inflammation upon fungal infection, and suppresses the activation of extracellular signal-regulated kinase (ERK) signaling by inhibiting ROS production. Thus, Hv1/VSOP is a two-way player regulating ROS production. Here, we review the functions of Hv1/VSOP in neutrophils and discuss future perspectives.

scholarly journals Voltage-Gated Proton Channels Find Their Dream Job Managing the Respiratory Burst in Phagocytes

Physiology ◽  
2010 ◽  
Vol 25 (1) ◽  
pp. 27-40 ◽  
Author(s):  
Thomas E. DeCoursey
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Respiratory Burst ◽  
Proton Channel ◽  
Oxygen Species ◽  
Proton Extrusion ◽  
Proton Channels ◽  
Voltage Gated ◽  
Voltage Gated Ion Channels ◽  
Voltage Sensing Domain

The voltage-gated proton channel bears surprising resemblance to the voltage-sensing domain (S1–S4) of other voltage-gated ion channels but is a dimer with two conduction pathways. The proton channel seems designed for efficient proton extrusion from cells. In phagocytes, it facilitates the production of reactive oxygen species by NADPH oxidase.

scholarly journals The proton channel HV1 is expressed in the medullary thick ascending limb of the kidney (1134.1)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Carly Stilphen ◽  
Jingping Sun ◽  
Nevin Lambert ◽  
Paul O’Connor
Keyword(s):  
Proton Channel ◽  
Thick Ascending Limb ◽  
Medullary Thick Ascending Limb

scholarly journals Voltage-gated proton channels exist in the plasma membrane of human oocytes

2019 ◽  
Vol 34 (10) ◽  
pp. 1974-1983 ◽  
Author(s):  
R Ya Smith ◽  
D Morgan ◽  
L Sharma ◽  
V V Cherny ◽  
N Tidswell ◽  
...  
Keyword(s):  
Large Scale ◽  
Human Sperm ◽  
Proton Channel ◽  
Human Oocytes ◽  
Proton Channels ◽  
Voltage Gated ◽  
Registration Number ◽  
Heterologous Expression Systems ◽  
Competing Interest ◽  
Proton Currents

Abstract STUDY QUESTION Do human oocytes express voltage-gated proton channels? SUMMARY ANSWER Human oocytes exhibit voltage-gated proton currents. WHAT IS KNOWN ALREADY Voltage-gated proton currents have been reported in human sperm, where they contribute to capacitation and motility. No such studies of human oocytes exist. STUDY DESIGN, SIZE, DURATION Voltage-clamp studies were undertaken using entire oocytes and vesicles derived from oocytes and in excised patches of membrane from oocytes. PARTICIPANTS/MATERIALS, SETTING, METHODS Frozen, thawed human metaphase II oocytes were obtained from material donated to the gamete repository at the Rush Center for Advanced Reproductive Care. Prior to patch clamping, oocytes were warmed and equilibrated. Formation of an electrically tight seal requires exposing bare oolemma. Sections of the zona pellucida (ZP) were removed using a laser, followed by repeated pipetting, to further separate the oocyte from the ZP. Patch-clamp studies were performed using the whole-cell configuration on oocytes or vesicles derived from oocytes, and using inside-out patches of membrane, under conditions optimized to detect voltage-gated proton currents. MAIN RESULTS AND THE ROLE OF CHANCE Proton currents are present at significant levels in human oocytes where they exhibit properties similar to those reported in other human cells, as well as those in heterologous expression systems transfected with the HVCN1 gene that codes for the voltage-gated proton channel. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Human oocytes are large cells, which limits our ability to control the intracellular solution. Subtle effects of cryopreservation by vitrification and subsequent warming on properties of HVCN1, the HVCN1 gene product, cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS Possible functions for voltage-gated proton channels in human oocytes may now be contemplated. STUDY FUNDING/COMPETING INTEREST(S) NIH R35GM126902 (TED), Bears Care (DM). No competing interests. TRIAL REGISTRATION NUMBER N/A.

scholarly journals Voltage and pH sensing by the voltage-gated proton channel, H V 1

2018 ◽  
Vol 15 (141) ◽  
pp. 20180108 ◽  
Author(s):  
Thomas E. DeCoursey
Keyword(s):  
Membrane Potential ◽  
Electrostatic Interactions ◽  
Proton Channel ◽  
Ph Sensing ◽  
Proton Channels ◽  
Voltage Gated ◽  
Charge Model ◽  
Conduction Pathway ◽  
Ph Range ◽  
Very High

Voltage-gated proton channels are unique ion channels, membrane proteins that allow protons but no other ions to cross cell membranes. They are found in diverse species, from unicellular marine life to humans. In all cells, their function requires that they open and conduct current only under certain conditions, typically when the electrochemical gradient for protons is outwards. Consequently, these proteins behave like rectifiers, conducting protons out of cells. Their activity has electrical consequences and also changes the pH on both sides of the membrane. Here we summarize what is known about the way these proteins sense the membrane potential and the pH inside and outside the cell. Currently, it is hypothesized that membrane potential is sensed by permanently charged arginines (with very high p K a ) within the protein, which results in parts of the protein moving to produce a conduction pathway. The mechanism of pH sensing appears to involve titratable side chains of particular amino acids. For this purpose their p K a needs to be within the operational pH range. We propose a ‘counter-charge’ model for pH sensing in which electrostatic interactions within the protein are selectively disrupted by protonation of internally or externally accessible groups.

scholarly journals Roles of Microglial Ion Channel in Neurodegenerative Diseases

2021 ◽  
Vol 10 (6) ◽  
pp. 1239
Author(s):  
Alexandru Cojocaru ◽  
Emilia Burada ◽  
Adrian-Tudor Bălșeanu ◽  
Alexandru-Florian Deftu ◽  
Bogdan Cătălin ◽  
...  
Keyword(s):  
Ion Channels ◽  
Neurodegenerative Diseases ◽  
Excitable Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
The Common ◽  
Transient Receptor ◽  
The Impact

As the average age and life expectancy increases, the incidence of both acute and chronic central nervous system (CNS) pathologies will increase. Understanding mechanisms underlying neuroinflammation as the common feature of any neurodegenerative pathology, we can exploit the pharmacology of cell specific ion channels to improve the outcome of many CNS diseases. As the main cellular player of neuroinflammation, microglia play a central role in this process. Although microglia are considered non-excitable cells, they express a variety of ion channels under both physiological and pathological conditions that seem to be involved in a plethora of cellular processes. Here, we discuss the impact of modulating microglia voltage-gated, potential transient receptor, chloride and proton channels on microglial proliferation, migration, and phagocytosis in neurodegenerative diseases.

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