# Mechanisms of Calcium-Calmodulin Mediated Ion Channel Gating

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $393,820

## Abstract

Project Summary
 As a central molecular hub in calcium signaling, calmodulin (CaM) is a key regulator of hundreds of target proteins
including a wide range of ion channels. Essential for understanding the diversity of calmodulin mediated cellular
processes is a thorough understanding of the physical relationships and interactions between calcium ions, the four EF-
hand binding sites of calmodulin and the individual target proteins. We have developed new methods that allow the
characterization of the four binding sites individually, including their binding affinities and cooperative interactions. Our
previous work has shown, by site-specific binding measurements and evolutionary informatics that CaM's four EF-hand
binding sites have different and distinct binding properties that have undergone strong selective pressures to remain
different from each other. The overall goal of this proposal is to employ new state of the art experimental and analytic
methods to understand the energetics and molecular mechanisms of calcium binding at each binding sites and how
they are altered by occupancy at neighboring sites (cooperativity) and by binding to targets (transduction). We bring to
these efforts powerful new experimental and theoretical approaches that we have developed that promise to lead to an
unprecedented understanding of the CaM signal transduction mechanism that will have implications for ion channel
regulation, calcium signaling and allosteric mechanisms in general. Our aims are to: (1) Determine by lanthanide
luminescence spectroscopy the site-specific affinity and cooperativity of Ca2+ and Ln3+ binding to each of the four EF
hands of free CaM in solution; (2) Determine how each of the four EF-hand ligand binding affinities are changed upon
binding to specific target proteins or appropriate peptide fragments and how calmodulin peptide affinity and
stoichiometry are modulated by calcium binding; (3) Determine the amino attributes that determine the unique
binding properties of the four EF hand Ca2+ binding sites in CaM using lanthanide luminescence spectroscopy on
calmodulin binding site chimeras.

## Key facts

- **NIH application ID:** 10217262
- **Project number:** 5R01NS077821-10
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Richard Aldrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,820
- **Award type:** 5
- **Project period:** 2011-09-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217262

## Citation

> US National Institutes of Health, RePORTER application 10217262, Mechanisms of Calcium-Calmodulin Mediated Ion Channel Gating (5R01NS077821-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10217262. Licensed CC0.

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