# Mechanisms of Compartmentalized cAMP Signaling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $405,507

## Abstract

Title: Mechanisms of Compartmentalized cAMP Signaling
Project summary:
 The overall goal of the proposed research is to provide a mechanistic understanding about how cyclic
AMP (cAMP) regulates a variety of different cellular functions with exquisite specificity. As a ubiquitous second
messenger, cAMP regulates a variety of processes that are critical to cell physiology, such as cell growth,
proliferation, metabolism, survival and mobility. In pancreatic β cells, cAMP is produced in response to glucose
or hormones such as glucagon-like peptide-1 (GLP-1), and in turn modulates the Ca2+ signal, directly
influencing exocytotic insulin release as well as regulating gene expression, acting through its effector
molecules cAMP-dependent protein kinase (PKA) and exchange proteins activated by cAMP (Epac). The
concept of “cAMP compartmentation”, wherein unique changes in second messenger levels and effector
activities occur in both space and time, was put forward to help understand the exquisite signaling specificity of
cAMP, yet the mechanisms underlying cAMP compartmentation remain elusive.
 In the previous funding period, we made a breakthrough discovery. We discovered that the PKA
regulatory subunit RIα undergoes liquid-liquid phase separation (LLPS) and that these condensates are critical
for cAMP compartmentation by serving as a dynamic buffering system, and allowing PDEs to create cAMP
microdomains. This discovery was enabled by the development of a new class of fluorescent biosensors that
can be targeted to proteins at the endogenous level, allowing probing of signaling dynamics at the native
stoichiometry. We have also created a novel class of fluorescent biosensors that allow direct visualization of
PKA activities in superresolution and elucidated how our previously discovered oscillatory circuit is regulated
spatially by A-Kinase Anchoring Protein 79/150. Altogether we published 29 peer-reviewed journal articles
(with 4 additional manuscripts in revision). In the current proposal, building on these discoveries, we will test
our hypothesis that PKA RIα phase separation, by sequestering cAMP and the catalytic subunit of PKA,
enables compartmentalized cAMP signaling and allows cAMP to achieve high signaling specificity and
functional diversity in β cells. Specifically, we will develop novel molecular tools to interrogate the
spatiotemporal regulation of cAMP/PKA signaling in living cells, examine the impact of RIα phase separation
on cAMP/PKA signaling and determine the functional roles of RIα phase separation in β cells.
 Our proposed studies should lead to a better understanding of the molecular mechanisms and
functional roles of the spatiotemporal regulation of cAMP/PKA signaling, particularly in the context of the
regulation of  cell functions. As aberrations in the cAMP signaling pathway are implicated in clinical conditions
such as obesity and type 2 diabetes mellitus, such an understanding should help identify sites of dysfunction in
type ...

## Key facts

- **NIH application ID:** 10210807
- **Project number:** 2R01DK073368-16
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,507
- **Award type:** 2
- **Project period:** 2006-01-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210807

## Citation

> US National Institutes of Health, RePORTER application 10210807, Mechanisms of Compartmentalized cAMP Signaling (2R01DK073368-16). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10210807. Licensed CC0.

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