# Molecular signal transduction of cAMP compartments

> **NIH NIH R01** · CHAPMAN UNIVERSITY · 2022 · $300,426

## Abstract

A large number of G protein coupled receptors (GPCR) utilize cAMP as their second messenger to alter cell
function. In fact, in the same cell several different GPCR can increase cAMP, leading to the question of how
the cell interprets the signals from these receptors differently. The concept of cAMP compartmentation, where
the second messenger is not generated uniformly throughout the cell, is readily accepted yet poorly
understood. The enzymes that synthesize cAMP, adenylyl cyclases (ACs), are not uniformly distributed through
the plasma membrane. Furthermore, GPCR can preferentially couple to certain AC isoforms due to
colocalization in lipid rafts or non-raft domains. While we have made progress in understanding how specific
receptors can couple to different ACs, little progress has been made in defining the compartments of cAMP
inside cells and how cellular responses can be modified by different pools of cAMP. Commonly used cell
models are de-differentiated and lack highly compartmentized cAMP pools. However, we have defined two
clear cAMP signaling compartments in primary human airway smooth muscle (HASM) cells. The goal of this
project is to characterize the key regulatory components, PDEs and AKAPs, in these two cAMP compartments
and to discover novel protein members of signaling complexes therein. We will use siRNA to knockdown
individual PDEs and AKAPs then measure localized cAMP signals via novel fluorescent sensors. We have
defined the phosphoproteomic signatures of each cAMP compartment using quantitative phosphoproteomics,
so will leverage these signatures to infer roles for individual PDEs or AKAPs following knockdown. State-of-the-
art spectroscopic methods will directly assess the diffusion of cAMP in cells. Finally, we will use biotin proximity
labeling to identify AC-interacting proteins in both HASM and less well differentiated HEK-293 cells. This
project proposes innovative, multidisciplinary approaches to define the components responsible for
establishing and maintaining cAMP signaling compartments. Our findings will have broad applicability due to
the fundamental nature of cAMP signaling, but will also have direct relevance to asthma and COPD therapy.

## Key facts

- **NIH application ID:** 10438686
- **Project number:** 5R01GM107094-09
- **Recipient organization:** CHAPMAN UNIVERSITY
- **Principal Investigator:** RENNOLDS S OSTROM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,426
- **Award type:** 5
- **Project period:** 2015-01-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438686

## Citation

> US National Institutes of Health, RePORTER application 10438686, Molecular signal transduction of cAMP compartments (5R01GM107094-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438686. Licensed CC0.

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