# Structural Basis of Coupling and Dynamics in K+ Channels

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $501,478

## Abstract

Project Summary
In response to membrane potential depolarization, voltage-dependent channels undergo a series of
conformational changes from a non-conducting state (closed) to an activated (conducting), finally
stabilizing in a non-conducting inactivated state. K+ channel function has been associated with such basic
cellular functions as the regulation of electrical activity, signal transduction and osmotic balance. In higher
organisms, K+ channel dysfunction may lead to uncontrolled periods of electrical hyperexcytability, like
epileptic episodes, myotonia and cardiac arrhythmia. Consequently, efforts to understand K+ channel
structure function and dynamics relate directly to human health and disease. The continuing long-term
goal of this project is to further understand the molecular mechanisms of gating in voltage-dependent
channels, by focusing on the analysis of K+ channel gating in prokaryotic and eukaryotic systems.
Specifically we will address the following key questions: What are the atomic structures of the key
conformations that determine channel activity? This question will be answered for membrane embedded
systems as well as those ordered in a lattice. What are the molecular bases of voltage-dependent
gating? We will be testing the hypothesis that a specific sliding helix movement (the one click motion) can
explain charge translocation in certain voltage sensors, but perhaps not others. The more charge a sensor
translocates, the larger the number of clicks its sensor needs to move. And how different parts of the channel
interact to define open channel activity? We plan to study these problems by combining spectroscopic
techniques (EPR and NMR), X-ray crystallography electrophysiological and computational methods. We
intend to continue these structure-function studies by investigating a wealth of biochemically-defined
systems from KcsA and KvAP, to the Shaker voltage sensor and the hyperpolarization-activated channel
from Methanococcus janschii (MVP). In addition, we will focus our attention on the voltage-sensing
domain from the Ciona intestinalis-Voltage-Sensor-containing Phosphatase (Ci- VSP) aiming to improve the
resolution of our recent crystals structures. Finally, we will examine the structure of the human voltage-
dependent proton channel Hv1 in membranes though an extensive site-directed spin labeling analysis and
computational modeling. This proposal should open new experimental avenues that will contribute to our
understanding of biologically important events such as electrical signaling, signal transduction and ion
channel gating.

## Key facts

- **NIH application ID:** 10931367
- **Project number:** 5R01GM150272-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Eduardo A Perozo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $501,478
- **Award type:** 5
- **Project period:** 2023-09-20 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931367

## Citation

> US National Institutes of Health, RePORTER application 10931367, Structural Basis of Coupling and Dynamics in K+ Channels (5R01GM150272-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10931367. Licensed CC0.

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