# Role of mitochondria-associated spaces in the regulation of compartmentation of cAMP signaling

> **NIH NIH P20** · UNIVERSITY OF NEVADA RENO · 2021 · $207,657

## Abstract

Project Summary
Various G-protein-coupled receptors elicit distinct functional responses within a cell, even though they use the
common diffusible second messenger cAMP. For instance, while stimulation of either β-adrenergic receptors or
E-type prostaglandin receptors leads to cAMP production, only β-adrenergic receptors regulate cardiac myocyte
contractility. The ability of a cell to distinguish between cAMP produced in the same cell can only be explained if
engagement of different receptors generates distinct receptor-specific pools of cAMP. However, the underlying
mechanisms responsible for creating compartmentalized cAMP are not completely understood.
Compartmentalized cAMP signaling regulates cardiac contractility and thus is essential for normal functioning of
the heart. Consistent with this, dysregulation of cAMP compartmentalization has been linked to several
cardiovascular diseases, including cardiac arrhythmias, hypertrophy, and heart failure. Most previous studies
have focused on activities of phosphodiesterases, the enzymes that breakdown cAMP, to explain cAMP
compartmentation. However, several mathematical studies have predicted that PDE activity alone is not
sufficient. These studies have suggested that the mobility of cAMP must be slower than free diffusion to prevent
cAMP from reaching non-specific target proteins. We have recently demonstrated that the intracellular mobility
of cAMP is markedly hampered by buffering mediated by mitochondria-associated protein kinase A. Now, a new
computational study has predicted that, in addition to slow diffusion of cAMP, anatomically restricted spaces
within a cell are key to hindering cAMP movement. In cardiac myocytes, mitochondria occupy 30% of the cell
volume and are associated with constrained spaces through interactions with the sarcoplasmic reticulum and
cytoskeletal proteins. The overall aim of this proposal is to explore the concept that the tight spaces associated
with mitochondria regulate cAMP compartmentation. The tethering of mitochondria to the sarcoplasmic reticulum
by the proteins, mitofusin-2 (MFN2), glucose-regulated protein 75 (GRP75), and phosphofurin acidic cluster
sorting protein 2 (PACS2), creates tight spaces between these organelles. In the FIRST AIM of this study, we
will test the hypothesis that the anatomically restricted spaces between mitochondria and the sarcoplasmic
reticulum hinder cAMP movement and contribute to cAMP compartmentation. In cardiac myocytes, mitochondrial
arrangement is regulated by microtubules and muscle LIM protein (MLP). Disruption of microtubules or MLP
causes disorganization of mitochondria and alters mitochondrial morphology, thereby changing the cytosolic
spaces associated with mitochondria. Thus, in the SECOND AIM, we hypothesize that cAMP compartmentation
is hampered following mitochondrial derangement in microtubule-disrupted cells. To test these hypotheses, we
adopt multipronged and complementary approaches to study cAMP compartmenta...

## Key facts

- **NIH application ID:** 10077909
- **Project number:** 5P20GM130459-03
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** Shailesh Agarwal
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $207,657
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077909

## Citation

> US National Institutes of Health, RePORTER application 10077909, Role of mitochondria-associated spaces in the regulation of compartmentation of cAMP signaling (5P20GM130459-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10077909. Licensed CC0.

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