title: Modified cAMP derivatives: powerful tools in heart research.
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 isoproterenol, 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.
authors.affiliation: Department of Physiology, University of Debrecen, Nagyerdei krt. 98. H-4012 Debrecen, Hungary. norbi@phys.dote.hu
authors.forename: N
authors.initials: N
authors.lastname: Szentandrássy
authors.forename: G
authors.initials: G
authors.lastname: Harmati
authors.forename: V
authors.initials: V
authors.lastname: Farkas
authors.forename: B
authors.initials: B
authors.lastname: Horváth
authors.forename: B
authors.initials: B
authors.lastname: Hegyi
authors.forename: J
authors.initials: J
authors.lastname: Magyar
authors.forename: G
authors.initials: G
authors.lastname: Szénási
authors.forename: I
authors.initials: I
authors.lastname: Márton
authors.forename: P P
authors.initials: PP
authors.lastname: Nánási
mesh_terms: D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism; D004285:Dogs; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D020662:Guanine Nucleotide Exchange Factors; D024661:Potassium Channels, Inwardly Rectifying; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol