In vivo model with targeted cAMP biosensor reveals changes in receptor-microdomain communication in cardiac disease

Nat Commun. 2015 Apr 28;6:6965. doi: 10.1038/ncomms7965.

Abstract

3',5'-cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger that regulates physiological functions by acting in distinct subcellular microdomains. Although several targeted cAMP biosensors are developed and used in single cells, it is unclear whether such biosensors can be successfully applied in vivo, especially in the context of disease. Here, we describe a transgenic mouse model expressing a targeted cAMP sensor and analyse microdomain-specific second messenger dynamics in the vicinity of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). We demonstrate the biocompatibility of this targeted sensor and its potential for real-time monitoring of compartmentalized cAMP signalling in adult cardiomyocytes isolated from a healthy mouse heart and from an in vivo cardiac disease model. In particular, we uncover the existence of a phosphodiesterase-dependent receptor-microdomain communication, which is affected in hypertrophy, resulting in reduced β-adrenergic receptor-cAMP signalling to SERCA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists
  • Animals
  • Biosensing Techniques*
  • Calcium-Binding Proteins
  • Cardiomegaly / etiology
  • Cardiomegaly / metabolism
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Disease Models, Animal
  • Female
  • Fluorescence Resonance Energy Transfer
  • Guanine Nucleotide Exchange Factors
  • Heart Diseases / etiology
  • Heart Diseases / metabolism*
  • Isoproterenol
  • Mice, Transgenic
  • Myocytes, Cardiac / metabolism*
  • Phosphoric Diester Hydrolases / metabolism
  • Random Allocation
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*

Substances

  • Adrenergic beta-Agonists
  • Calcium-Binding Proteins
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • phospholamban
  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Isoproterenol

Associated data

  • GEO/GSE65651