# Replacement of essential core instrument that can no longer be supported for service contract

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $138,886

## Abstract

This project seeks to determine how voltage sensing domains control ion channel gating, a process
fundamental to all neuronal transmission, to control of endolysosomal delivery into cells, and recycling of
membrane proteins out to the plasma membrane. The aim is to determine the motion that is brought about
in voltage sensing domains upon activation based on the first atomic structures of a resting state and an
activated state in the same channel, an endolysosomal two-pore channel. The aim is to determine how this
structural change evoked upon voltage change is relayed to gate a central channel, by separating covalent
attachment by means of a direct protein sequence, from non-covalent interactions between the sensor and
the channel. The approach uses different two-pore channels, chemical cross linking, chemical trapping, and
mutations coupled to channel recordings, followed by atomic structural definition of intermediate states in
the process. With a related protein the aim is to visualize cellular complexes that associate with mucolipin in
the endolysosome. These partnerships impact many lysosomal and neuronal diseases and offer a map for
design of inhibitors of these processes that will lead the way to drugs that can be therapeutically
advantageous. The interactome of channels in the endolysosome offer an amazing network of connections
to disease that are a subject of this proposal. A second set of aims concerns how transmembrane
transporters, crucial to cell viability, transport essential nutrients into the cell, and function at the molecular
and structural level. By atomic structure determination of a transporter of essential phosphate, and others of
essential glucose, and of uric acid these transporters provide a roadmap to targeting these processes with
inhibitors and activators, that will be of therapeutic advantage in cancers, and are of use in regulating the
'master' regulators in the cell.

## Key facts

- **NIH application ID:** 10696846
- **Project number:** 3R01GM024485-45S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Robert M Stroud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $138,886
- **Award type:** 3
- **Project period:** 1979-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10696846

## Citation

> US National Institutes of Health, RePORTER application 10696846, Replacement of essential core instrument that can no longer be supported for service contract (3R01GM024485-45S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10696846. Licensed CC0.

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