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Membrane Microdomains and cAMP Compartmentation in Cardiac Myocytes

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Microdomains in the Cardiovascular System

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 3))

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Abstract

Signaling through the diffusible second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) is critical to the regulation of cardiac function. Several different G-protein-coupled receptors, including β-adrenergic receptors, muscarinic receptors, and E-type prostaglandin receptors, elicit distinct responses using this ubiquitous second messenger. One critical paradigm that has emerged to explain this behavior is that cAMP signaling is compartmentalized. Spatially confining specific receptors and their downstream effector proteins to form subcellular signaling complexes has been proposed to allow for the high efficiency and fidelity in producing specific functional responses. In cardiac myocytes, lipid rafts created by cholesterol- and sphingolipid-rich membrane microdomains have been demonstrated to act as one means of sorting appropriate receptors and corresponding effectors to relevant subcellular locations. Caveolae, which represent a specific subset of lipid rafts, can dynamically attract or exclude specific signaling proteins through a variety of mechanisms to create highly localized and self-sufficient multi-molecular signaling complexes. Furthermore, disruption of this organization in disease states such as heart failure has been found to alter cAMP responses. In this review, we summarize the current understanding of the role of membrane domains in cAMP signaling in cardiac myocytes. We also highlight the insights gained from previous studies to offer new avenues of research in this expanding field of study.

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Abbreviations

AC:

Adenylyl cyclase

ACh:

Acetylcholine

AKAP:

A-kinase-anchoring protein

cAMP:

3′,5′-Cyclic adenosine monophosphate

Cav3:

Caveolin 3

CSD:

Caveolin scaffolding domain

DRM:

Detergent-resistant membrane

EC:

Excitation-contraction

eNOS:

Endothelial nitric oxide synthase

Epac:

Exchange protein directly activated by cAMP

EPR:

E-type prostaglandin receptor

GPCR:

G-protein-coupled receptor

GPI:

Glycosylphosphatidylinositol

M2R:

M2 muscarinic receptor

MβCD:

Methyl-β-cyclodextrin

NO:

Nitric oxide

PDE:

Phosphodiesterase

PKA:

Protein kinase A

PLB:

Phospholamban

SICM:

Scanning ion conductance microscopy

SR:

Sarcoplasmic reticulum

T tubule:

Transverse tubule

β1AR:

β1-Adrenergic receptor

β2AR:

β2-Adrenergic receptor

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Acknowledgements

This work was supported by the National Institutes of Health grants GM101928 and GM107094.

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Conflict of Interest Statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, University of Nevada School of Medicine, Reno, NV, 89557, USA

    Shailesh R. Agarwal & Robert D. Harvey

  2. Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, 92618, USA

    Rennolds S. Ostrom

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  1. Shailesh R. Agarwal
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  2. Rennolds S. Ostrom
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  3. Robert D. Harvey
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Correspondence to Robert D. Harvey .

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Editors and Affiliations

  1. Institute of Experimental Cardiovascular Research, University Medical Center, Hamburg-Eppendorf, Germany

    Viacheslav Nikolaev

  2. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Manuela Zaccolo

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Agarwal, S.R., Ostrom, R.S., Harvey, R.D. (2017). Membrane Microdomains and cAMP Compartmentation in Cardiac Myocytes. In: Nikolaev, V., Zaccolo, M. (eds) Microdomains in the Cardiovascular System. Cardiac and Vascular Biology, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-54579-0_2

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