# Structural energetics of voltage- and ligand-dependent gating in ion channels

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2024 · $250,000

## Abstract

Abstract
Ion channels are exquisite molecular machines that regulate the flow of ions across cell membranes in
response to stimuli such as voltage and small molecule ligands (e.g. second messengers, and
neurotransmitters). They underlie all electrical excitability in the brain and heart, and defects in ion channels
are responsible for many human disorders. Despite decades of experiments and many high-resolution
molecular structures, we still do not know, for any channel, the mechanisms for voltage- or ligand-dependent
gating. The missing ingredient is conformational energetics. The energetics of the different channel
conformations governs the time course, voltage dependence, and ligand dependence of opening of the
channel pore, and ultimately electrical excitability of the cell. In the parent grant, our goals are to determine the
mechanisms of voltage-dependent gating and ligand-dependent gating and, ultimately, to understand the
general themes that underlie allosteric regulation of ion channels. Our approach has been to leverage
breakthrough FRET methods we developed for measuring intramolecular distance distributions and
conformational energetics using fluorescence lifetimes. One limitation of this approach is that it can only
measure equilibrium energetics. To truly determine the structural dynamics and energetics, we need to
measure the rates of the conformational transitions in the protein. To measure conformational transition rates
at steady state, we need to perform single-molecule experiments. This proposal is for a PicoQuant MicroTime
100 upgrade to our current PicoQuant system, previously purchased with the parent award, that would allow us
to do time-resolved confocal microscopy to measure single-molecule FRET. The requested equipment will
further accelerate our progress toward the goals of the parent grant.

## Key facts

- **NIH application ID:** 11031698
- **Project number:** 3R35GM148137-02S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** William N Zagotta
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $250,000
- **Award type:** 3
- **Project period:** 2023-01-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11031698

## Citation

> US National Institutes of Health, RePORTER application 11031698, Structural energetics of voltage- and ligand-dependent gating in ion channels (3R35GM148137-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11031698. Licensed CC0.

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