# Control Mechanisms of Human Voltage Gated Proton Channels, hHv1

> **NIH NIH R35** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $368,950

## Abstract

Project Summary/Abstract
The voltage gated proton channel (HV1) exists in many human tissues and plays numerous roles vital
to human health. For example, it contributes to bacterial killing by white blood cells, sperm
maturation and mobility, histamine release by basophils, B lymphocyte signaling, and airway fluid
regulation. Abnormal HV1 function has been implicated in breast cancer metastasis, brain damage in
ischemic stroke, and exacerbation of chronic lymphocytic leukemia. As its gene was not reported
until 2006, HV1 is a newcomer to the voltage gated ion channel family. Finally, its structure is unique
in resembling a crucial component of all voltage-gated ion channels. This newcomer status, its
unique structure, and its essential roles in human health and disease make understanding HV1
function and dysfunction highly significant.
 Directly translational studies will evaluate reported involvement of HV1 in breast cancer growth
and metastasis. Tumor growth in mice will be examined using cells with different HV1 expression
levels, ranging from complete knock-out (CRISPR/Cas9) to reduced (shRNA) to normal (WT). Our
current working hypothesis is that HV1 acts as a switch that transduces membrane potential changes
into cellular pathology. We will also build on our discovery of the involvement of HV1 in human B cells
and in chronic lymphocytic leukemia. A novel approach will be to determine the effects of mutations
indentified in human subjects with B cell malignancy.
 The DeCoursey lab has been deeply involved in the study of HV1, from discovering its
existence in mammalian and human cells, to identifying its role in a number of human cells and
tissues, to finally dissecting the molecule itself to identify which parts perform the major functions.
Over the next five years we intend to pursue expanding our knowledge of this important molecule at
multiple levels, building on our recent progress. We found that the mechanism producing proton
selective conduction requires an aspartate in the center of the pore. We will test whether a
hydrophobic region plays an additional critical role using mutagenesis, patch-clamp, and molecular
dynamics simulations. We will attack the mechanisms of voltage-gating and the unique ∆pH
dependent gating that is essential to all functions of this molecule using similar approaches, but
including a detailed mechanistic model as well as a newly improved molecular dynamics approach
that determines protonation empirically rather than assuming it. We will continually refine our
knowledge of the structures of both closed and open HV1 channels, using histidine scanning
mutagenesis and NMR. Structure-function knowledge is crucial both for understanding mechanisms
and for drug design.

## Key facts

- **NIH application ID:** 10145720
- **Project number:** 5R35GM126902-04
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** THOMAS E DECOURSEY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,950
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145720

## Citation

> US National Institutes of Health, RePORTER application 10145720, Control Mechanisms of Human Voltage Gated Proton Channels, hHv1 (5R35GM126902-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10145720. Licensed CC0.

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