Consequences of Dimerization of the Voltage-Gated Proton Channel

2015

Biochemistry

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The main properties of voltage gated proton channels are described, along with what is known about how the channel protein structure accomplishes these functions. Just as protons are unique among ions, proton channels are unique among ion channels. Their four transmembrane helices sense voltage, the pH gradient, and conduct protons exclusively. Selectivity is achieved by the unique ability of H3O+ to protonate an Asp-Arg salt bridge. Pathognomonic sensitivity of gating to the pH gradient ensures channel opening only when acid extrusion will result, which is crucial to most biological functions. An exception occurs in dinoflagellates in which H+ influx through HV1 triggers the bioluminescent flash. Pharmacological interventions that promise to ameliorate cancer, asthma, brain damage in ischemic stroke, Alzheimer’s disease, autoimmune diseases, and numerous other conditions, await future progress.

Section: Why Are Mammalian Hv1 Dimers?mentioning

confidence: 76%

Section: Why Are Mammalian Hv1 Dimers?mentioning

confidence: 99%

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

2015

Biochemistry

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“…In contrast, H V 1 consists of S1–S4 alone, a VSD without an explicit pore domain ( Ramsey et al, 2006 ; Sasaki et al, 2006 ). In mammals and many other species ( Koch et al, 2008 ; Lee et al, 2008 ; Tombola et al, 2008 ; Smith and DeCoursey, 2013 ), H V 1 forms a dimer in cell membranes. However, each monomer, or protomer, has its own pore and other necessary parts and can function as a monomer ( Koch et al, 2008 ; Tombola et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

“…The properties of monomeric constructs are similar in most respects to those of the dimer, but monomeric constructs open faster ( Koch et al, 2008 ; Tombola et al, 2008 ; Musset et al, 2010b , c ; Fujiwara et al, 2012 ). Several lines of evidence indicate that the two protomers comprising the H V 1 dimer do not function independently, but gate cooperatively in the sense that each must undergo a voltage-dependent conformational change before either can conduct current ( Gonzalez et al, 2010 ; Musset et al, 2010b ; Tombola et al, 2010 ; Smith and DeCoursey, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Insights into the structure and function of HV1 from a meta-analysis of mutation studies

Journal of General Physiology

Morgan

Musset

et al. 2016

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The voltage-gated proton channel (HV1) is a widely distributed, proton-specific ion channel with unique properties. Since 2006, when genes for HV1 were identified, a vast array of mutations have been generated and characterized. Accessing this potentially useful resource is hindered, however, by the sheer number of mutations and interspecies differences in amino acid numbering. This review organizes all existing information in a logical manner to allow swift identification of studies that have characterized any particular mutation. Although much can be gained from this meta-analysis, important questions about the inner workings of HV1 await future revelation.

“…Progress on H V 1 was quite rapid, and will be summarized only briefly here because of its limited relevance to our main topic. In rapid succession, it was discovered that H V 1 is a dimer both in heterologous expression systems (229)(230)(231)(232) and in situ in phagocytes (133), although each protomer has a separate conduction pathway (229,231), and the monomer functions almost normally but with faster opening kinetics (229,231,233,234); the dimer was found to open cooperatively (235-237); a knockout mouse was produced and found to appear grossly normal but with distinct deficiencies (44,(134)(135)(136)(137)(138)217); a 'signature sequence' of amino acids was identified as RxWRxxR in the S4 helix that has enabled the discovery of several new H V 1 (153); the phosphorylation site responsible for enhanced gating was identified as Thr 29 on the intracellular N terminus (96,224); and the selectivity mechanism was elucidated in which Asp-Arg interaction is crucial (153,(238)(239)(240)(241). A crystal structure of the closed mouse H V 1 has been reported (174), but the open state structure relies on homology models (239,(242)(243)(244)(245)(246) and EPR measurements (247,248).…”

Section: What the Discovery Of The Hvcn1 Gene Meantmentioning

confidence: 99%

The intimate and controversial relationship between voltage‐gated proton channels and the phagocyte NADPH oxidase

2016

Immunological Reviews

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Summary One of the most fascinating and exciting periods in my scientific career entailed dissecting the symbiotic relationship between two membrane transporters, the NADPH oxidase complex and voltage gated proton channels (HV1). By the time I entered this field, there had already been substantial progress toward understanding NADPH oxidase, but HV1 were known only to a tiny handful of cognoscenti around the world. Having identified the first proton currents in mammalian cells in 1991, I needed to find a clear function for these molecules if the work was to become fundable. The then-recent discoveries of Henderson, Chappell, and colleagues in 1987–1988 that led them to hypothesize interactions of both molecules during the respiratory burst of phagocytes provided an excellent opportunity. In a nutshell, both transporters function by moving electrical charge across the membrane: NADPH oxidase moves electrons and HV1 moves protons. The consequences of electrogenic NADPH oxidase activity on both membrane potential and pH strongly self-limit this enzyme. Fortunately, both consequences specifically activate HV1, and HV1 activity counteracts both consequences, a kind of yin-yang relationship. Notwithstanding a decade starting in 1995 when many believed the opposite, these are two separate molecules that function independently despite their being functionally interdependent in phagocytes. The relationship between NADPH oxidase and HV1 has become a paradigm that somewhat surprisingly has now extended well beyond the phagocyte NADPH oxidase -- an industrial strength producer of reactive oxygen species (ROS) -- to myriad other cells that produce orders of magnitude less ROS for signaling purposes. These cells with their seven NADPH oxidase (NOX) isoforms provide a vast realm of mechanistic obscurity that will occupy future studies for years to come.