# Integration of cAMP and TRPV4 Signaling to Optimize Collagen Remodeling for Management of Fibrosis

## TL;DR

The paper explores how cAMP and TRPV4 signaling interact to influence collagen remodeling and fibrosis, suggesting a new approach combining Gαs GPCR activation and TRPV4 inhibition.

## Contribution

The study reveals a novel bimodal therapeutic strategy for fibrosis by coordinating Gαs GPCR activation and TRPV4 inhibition.

## Key findings

- Gαs GPCRs generate cAMP, which inhibits fibrotic processes by optimizing collagen degradation.
- Dysregulated TRPV4 promotes myofibroblast differentiation and reduces β1 integrin expression.
- Coordinated activation of Gαs GPCR and inhibition of TRPV4 may control tissue fibrosis.

## Abstract

What are the main findings?
Gαs GPCRs generates cAMP, which inhibits fibrotic processes by optimizing intracellular collagen degradation and remodeling.TRPV4 activation regulates collagen remodeling under physiological conditions, but when dysregulated, TRPV4 promotes myofibroblast differentiation and reduces β1 integrin expression.

Gαs GPCRs generates cAMP, which inhibits fibrotic processes by optimizing intracellular collagen degradation and remodeling.

TRPV4 activation regulates collagen remodeling under physiological conditions, but when dysregulated, TRPV4 promotes myofibroblast differentiation and reduces β1 integrin expression.

What are the implications of the main findings?
Ca2+ influx through TRP channels modulates cAMP levels by regulating phosphodiesterases and adenylyl cyclases, underpinning the interplay between these signaling systems.Coordinated activation of the Gαs GPCRs pathway and inhibition of TRPV4 may provide a novel, bimodal approach to control tissue fibrosis.

Ca2+ influx through TRP channels modulates cAMP levels by regulating phosphodiesterases and adenylyl cyclases, underpinning the interplay between these signaling systems.

Coordinated activation of the Gαs GPCRs pathway and inhibition of TRPV4 may provide a novel, bimodal approach to control tissue fibrosis.

Fibrosis manifests as an excessive accumulation of fibrillar collagen in tissues where secreted collagen exceeds degradation. Myofibroblasts are important contributors to the excessive collagen seen in fibrotic lesions. Accordingly, targeting signaling pathways that enhance collagen degradation and subdue myofibroblast differentiation has the potential to optimize collagen remodeling and improve organ fibrosis. One of the most promising molecular targets for therapeutic development is the G protein-coupled receptor (GPCR) family, which is diverse, cell-type-specific, multi-pass transmembrane receptors that participate in the regulation of extracellular matrix remodeling. GPCRs are categorized into multiple subclasses, some of which activate signaling cascades that can augment or reduce pro-fibrotic processes, depending on which Gα class is activated. Specifically, activation of Gαs GPCR stimulates production of the second messenger, cyclic adenosine monophosphate (cAMP), which generally inhibits pro-fibrotic mediators. A related, second approach for control of fibrosis is the blockade of a specific mechanosensitive, Ca2+-permeable channel that is implicated in fibrosis and contributes to myofibroblast differentiation, the transient receptor potential vanilloid type 4 (TRPV4). In health, TRPV4 activation regulates collagen remodeling, but when dysregulated, it promotes pro-fibrotic gene expression through mechanosensitive transcription factors. In this review, we focus on the functions of the Gαs GPCR pathway and TRPV4 activation through the interplay of the second messengers cAMP and Ca2+ ions. Ca2+ influx modulates cAMP levels by regulating phosphodiesterases and adenylyl cyclases. We consider evidence that Gαs GPCR and TRPV4 signaling pathways interact antagonistically to either promote collagen degradation or to increase the formation of myofibroblasts through signaling that involves cAMP and Ca2+ conductance. Coordinated activation of the Gαs GPCR pathway and inhibition of TRPV4 could provide a novel, bimodal approach to control tissue fibrosis.