The voltage gated proton channel (hHV1) plays crucial roles in many cells in the human body. It enables rapid activity of the enzyme NADPH oxidase that produces reactive oxygen species (ROS). ROS produced by NADPH oxidase in white blood cells help kill bacteria, fungi, parasites, and other microbial invaders. However, in some situations, cells produce too much ROS, which results in a wide variety of intractable pathologies linked to inflammation damage, including neurodegenerative and fibrotic diseases (e.g., Alzheimer's disease), some cancers, atherosclerosis, hypertension, and tissue rejection. hHV1 function thus impacts numerous inflammation-associated degenerative diseases for which cures and treatments are inadequate or nonexistent. Because the innate immune response to microbial pathogens must be preserved, strategies to control ROS must not abolish ROS production completely. The proton channel is an ideal drug target, because eliminating its activity reduces but does not abolish ROS production by white cells. In addition to its effect on ROS, hHV1 has other functions in basophils, nasal mucosa, sperm, and B cells that implicate it in male fertility, allergic responses, and such diseases as cystic fibrosis, asthma, and lupus. Thus, interventions that modulate hHV1 could act as antihistamines, provide treatments of asthma, and serve as male contraceptives. A recent report indicates high hHV1 expression in metastatic breast cancer tissues, and showed that metastatic invasion was reduced by lowering hHV1 levels. This finding suggests the possibility of stopping breast cancer by hHV1 inhibition. This project will determine the key to how the proton channel does its job, which is moving protons across cell membranes, while excluding all other ions. We recently discovered the location of the """"""""selectivity filter"""""""" of the proton channel, but the mechanism of its fundamental characteristic, extreme proton selectivity, remains enigmatic. The molecular details of this mechanism, which we will investigate in the proposed work, will provide the essential information needed to design therapies directed against hHV1 function. We will change specific parts of the protein and investigate the effects of the changes experimentally. We will also use computer modeling to predict and explain the proton selectivity mechanism. In collaboration with Drs. Nadim Hallab and Joshua Jacobs (Rush University Medical Center), we will use artificial joint rejection as a pathophysiological model of hHV1 function. We will alter hHV1 function in ways that future drugs might, and we will evaluate effects on both individual cells and the physiological system.

Public Health Relevance

This project will identify the crucial parts of the proton channel molecule so drugs to regulate its function can be developed. Modulating proton channels could help white blood cells kill bacteria, enable male contraception, and prevent or treat neurodegenerative and fibrotic diseases, breast cancer, atherosclerosis, hypertension, and tissue rejection.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-N (05))
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Nie, Zhongzhen
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Rush University Medical Center
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DeCoursey, Thomas E; Morgan, Deri; Musset, Boris et al. (2016) Insights into the structure and function of HV1 from a meta-analysis of mutation studies. J Gen Physiol 148:97-118
DeCoursey, Thomas E (2016) The intimate and controversial relationship between voltage-gated proton channels and the phagocyte NADPH oxidase. Immunol Rev 273:194-218
Dudev, Todor; Musset, Boris; Morgan, Deri et al. (2015) Selectivity Mechanism of the Voltage-gated Proton Channel, HV1. Sci Rep 5:10320
DeCoursey, Thomas E (2015) Publishing: Double-blind peer review a double risk. Nature 520:623
Cherny, Vladimir V; Morgan, Deri; Musset, Boris et al. (2015) Tryptophan 207 is crucial to the unique properties of the human voltage-gated proton channel, hHV1. J Gen Physiol 146:343-56
DeCoursey, Thomas E (2015) The Voltage-Gated Proton Channel: A Riddle, Wrapped in a Mystery, inside an Enigma. Biochemistry 54:3250-68
DeCoursey, Thomas E (2015) Structural revelations of the human proton channel. Proc Natl Acad Sci U S A 112:13430-1
DeCoursey, Thomas E; Hosler, Jonathan (2014) Philosophy of voltage-gated proton channels. J R Soc Interface 11:20130799
Hondares, Elayne; Brown, Mark Adrian; Musset, Boris et al. (2014) Enhanced activation of an amino-terminally truncated isoform of the voltage-gated proton channel HVCN1 enriched in malignant B cells. Proc Natl Acad Sci U S A 111:18078-83
Morgan, Deri; Musset, Boris; Kulleperuma, Kethika et al. (2013) Peregrination of the selectivity filter delineates the pore of the human voltage-gated proton channel hHV1. J Gen Physiol 142:625-40

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