The Development of Compartmentation of cAMP Signaling in Cardiomyocytes: The Role of T-Tubules and Caveolae Microdomains.

Navneet Bhogal,Julia Gorelik,Alveera Hasan

doi:10.3390/jcdd5020025

Navneet Bhogal, Julia Gorelik + Show 1 more

Open Access

https://doi.org/10.3390/jcdd5020025

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Abstract

3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, cAMP is also involved in multiple other functions. Compartmentation of cAMP production may explain the specificity of signaling following a stimulus. In particular, transverse tubules (T-tubules) and caveolae have been found to be critical structural components for the spatial confinement of cAMP in cardiomyocytes, as exemplified by beta-adrenergic receptor (β-ARs) signaling. Pathological alterations in cardiomyocyte microdomain architecture led to a disruption in compartmentation of the cAMP signal. In this review, we discuss the difference between atrial and ventricular cardiomyocytes in respect to microdomain organization, and the pathological changes of atrial and ventricular cAMP signaling in response to myocyte dedifferentiation. In addition, we review the role of localized phosphodiesterase (PDE) activity in constraining the cAMP signal. Finally, we discuss microdomain biogenesis and maturation of cAMP signaling with the help of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Understanding these mechanisms may help to overcome the detrimental effects of pathological structural remodeling.

Highlights

The fascination about 3 -5 -cyclic adenosine monophosphate, a second messenger molecule, is with its ability to activate multiple signalling pathways having different effects on cellular physiology in many cell types
The localized synthesis of cyclic adenosine monophosphate (cAMP) by one of 10 different adenylate cyclase (AC) isoforms is crucial in providing initial first step in signalling cascade, the manner in which cAMP is compartmentalized within the cell is essential to elicit a specific cellular response
It was found that β2ARs are the primary source of cAMP/protein kinase A (PKA) signalling in “early” cardiomyocytes; whereas increasing time in culture leads to the β1-AR dependent cAMP production to increase to 60% rise from day 30 to day 60 [99]

Summary

Introduction

The fascination about 3 -5 -cyclic adenosine monophosphate (cAMP), a second messenger molecule, is with its ability to activate multiple signalling pathways having different effects on cellular physiology in many cell types. Buxton and Bruton indicated a paradox whereby stimulation of a cell via various receptor pathways provided diverse cellular responses despite generating the same cAMP second messenger [3]. It was further elucidated, that these multiple spatially confined cAMP compartments may be the result of different protein kinase A (PKA) isoforms and other cAMP-sensitive downstream targets having restricted access to cAMP [4]. The main catecholamine-responsive receptors on the surface of cardiac myocytes are β-adrenergic receptors (β-ARs), an important class of G-protein-coupled receptors (GPCR) To generate these responses, β-ARs are coupled to Gs proteins, which activate AC and, induce cAMP production. The differing effects on cardiac function upon gene ablation suggests that these AC isoforms provide different functions to the heart

Transverse Axial Tubular System

Caveolae

Microdomains of cAMP Signalling in Healthy Ventricular Myocytes

PDEs and cAMP Compartmentation in Ventricular Myocytes

Findings

10. Conclusions