# Regulation and Dysregulation of Cardiac EC coupling by Calmodulin

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $787,498

## Abstract

Abstract
 The small Ca binding protein, calmodulin (CaM), either directly controls, or at minimum, modulates every
functionality within the heart. This versatile and ubiquitous Ca binding protein is the only known exception to the
central rule of biology - one gene one protein. In all mammalian cells, an identical CaM protein is derived from
three different genes, CaM1,2 and 3. Finding the reason for this deviation is not only important to explain this
biological conundrum, but for understanding the vast signaling processes mediated by CaM in various cell types
including cardiac myocytes in health and disease. CaM is known to bind and regulate hundreds of target proteins.
Due to the fact that the free concentration of CaM is limited within cardiac myocytes, yet the bound protein is
abundant, we surmise the presence of the three different genes is important for orchestrating specific and unique
myocyte CaM-mediated Ca signaling processes in space and time. We propose the divergent 5’ and 3’ UTRs
of the three CaM genes recruit different RNA binding proteins used to transport and pool together specific CaM
target proteins’ mRNAs into discrete “interactosomes”. We hypothesize these mRNA clusters are then locally
translated together (“tranlatosomes”) where the proteins function within the cardiac myocyte and are thus
“functionally distributed”. We have created novel imaging tools and data analysis software in order to visualize
these processes. We have also discovered in the adult cardiac myocyte that ribosomal translocons, rough ER,
and the golgi complex actively process and translate transmembrane proteins far from the perinuclear space,
contradictory to the long held classical view of membrane protein translation. In this proposal, we will define the
abundance, subcellular distribution, sites of translation and physiological modulation for the three CaM mRNAs,
along with key CaM targets in cardiac myocytes in health and disease. Ultimately, we will apply this novel and
new knowledge to target our therapeutically engineered proteins with high precision and specificity to select
“interactosomes” in order to treat various cardiovascular diseases.

## Key facts

- **NIH application ID:** 10445513
- **Project number:** 2R01HL138579-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jonathan Paul Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $787,498
- **Award type:** 2
- **Project period:** 2017-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445513

## Citation

> US National Institutes of Health, RePORTER application 10445513, Regulation and Dysregulation of Cardiac EC coupling by Calmodulin (2R01HL138579-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10445513. Licensed CC0.

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