# Regulation of Adenylyl Cyclase Signaling Pathways

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $428,410

## Abstract

Project Summary
Cyclic AMP is a universal second messenger and is essential for the chronotropic, inotropic and lusitropic
effects during the `fight-or-flight' response. Dysregulation of cAMP signaling induces hypertrophic growth and
ventricular dysfunction, eventually leading to heart failure. Adenylyl cyclase (AC) production of cAMP is
controlled on many levels, including the formation of macromolecular complexes that generate localized pools
of cAMP. Disorganization of cAMP compartmentation and a loss of hormonal specificity occur in models of
chronic heart failure, suggesting a mechanism for the cardiotoxic effects of the cAMP pathway. We have
previously identified multiple cardiac A-kinase anchoring proteins (AKAPs) that scaffold AC near upstream and
downstream signaling partners to provide a means of spatial and temporal regulation of cAMP and cardiac
function. But is AKAP scaffolding required for all cAMP effectors? We hypothesize that 1) AKAP-independent
anchoring of AC to effector complexes is a major contributor to cAMP sensitivity and 2) both AKAP-dependent
and AKAP-independent macromolecular AC-effector complexes are required for cardiac function. In support of
this hypothesis, we have identified a new AC scaffolding protein, the Popeye Domain-Containing protein,
Popdc. Popdc isoforms are transmembrane proteins that are important for pacemaker function, reperfusion
injury, and muscle regeneration. Importantly, Popdc represents a novel cAMP effector, with a cytosolic cAMP
binding domain that regulates protein-protein interactions. Clinically, mutation of human Popdc1 (S201F)
reduces cAMP binding by 50% and causes Limb-Girdle Muscular Dystrophy and Cardiac Arrhythmia. In
sinoatrial node, cAMP-dependent Popdc regulation of the potassium channel TREK-1 acts to control heart
rate. Our recent studies of AC9-/- mice show that AC9 is also an important regulator of basal cardiac function
and heart rate, while preliminary data show a complex of AC9-Popdc-TREK. Additionally, Popdc regulates AC9
activity in a cAMP-dependent manner. Thus, the Popdc proteins have all the scaffolding, feedback, and
effector regulatory properties that AKAP-PKA complexes create, but bundled in one unique protein. Three
specific aims are proposed to examine the role of this novel AC complex on cardiac function. Aim 1, Identify
specificity and interaction sites for AC-Popdc complexes. Aim 2, Determine the mechanism of Popdc regulation
of AC activity. Aim 3, Examine functional roles for AC-Popdc complexes in heart. Our studies have important
implications not only for cardiac muscle, but for skeletal muscle regulation and possibly additional AC isoforms.

## Key facts

- **NIH application ID:** 9838226
- **Project number:** 5R01GM060419-20
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Carmen W. Dessauer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,410
- **Award type:** 5
- **Project period:** 2000-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838226

## Citation

> US National Institutes of Health, RePORTER application 9838226, Regulation of Adenylyl Cyclase Signaling Pathways (5R01GM060419-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838226. Licensed CC0.

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