Modified cAMP derivatives: Powerful tools in heart research

N. Szentandrássy, G. Harmati, V. Farkas, B. Horváth, B. Hegyi, J. Magyar, G. Szénási, I. Márton, P. P. Nánási

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Receptor-mediated changes in intracellular cyclic AMP concentration play critical role in the autonomic control of the heart, including regulation of a variety of ion channels via mechanisms involving protein kinase A, EPAC, or direct actions on cyclic nucleotide gated ion channels. In case of any ion channel, the actual signal transduction cascade can be identified by using properly modified cAMP derivatives with altered binding and activating properties. In this study we focus to structural modifications of cAMP resulting in specific activator and blocking effects on PKA or EPAC. Involvement of the cAMP-dependent signal transduction pathway in controlling rapid delayed rectifier K + current was studied in canine ventricular myocytes using these specific cAMP analogues. Adrenergic stimulation increased the density of I Kr in canine ventricular cells, which effect was mediated by a PKA-dependent but EPAC-independent pathway. It was also shown that intracellular application of large concentrations of cAMP failed to fully activate PKA comparing to the effect of iso-proterenol, forskolin, or PDE-resistant cAMP derivatives. This difference was fully abolished following inhibition of phosphodiesterase by IBMX. These results are in line with the concept of compartmentalized release, action, and degradation of cAMP within signalosomes.

Original languageEnglish
Pages (from-to)3729-3736
Number of pages8
JournalCurrent medicinal chemistry
Volume18
Issue number24
DOIs
Publication statusPublished - Aug 1 2011

Keywords

  • Adrenergic stimulation
  • CAMP analogues
  • Dog myocytes
  • EPAC
  • Intracellular compartmentalization
  • Phosphodiesterase
  • Protein kinase A
  • Rapid delayed rectifier K current

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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