Cyclic AMP compartmentation due to increased cAMP-phosphodiesterase activity in transgenic mice with a cardiac-directed expression of the human adenylyl cyclase type 8 (AC8).
Hearts from AC8TG mice develop a higher contractility (LVSP) and larger Ca2+ transients than NTG mice, with (surprisingly) no modification in L-type Ca2+ channel current (ICa,L) (1). In this study, we examined the cardiac response of AC8TG mice to beta-adrenergic and muscarinic agonists and IBMX, a cyclic nucleotide phosphodiesterase (PDE) inhibitor. Stimulation of LVSP and ICa,L by isoprenaline (ISO, 100 nM) was twofold smaller in AC8TG vs. NTG mice. In contrast, IBMX (100 microM) produced a twofold higher stimulation of ICa,L in AC8TG vs. NTG mice. IBMX (10 microM) increased LVSP by 40% in both types of mice, but contraction and relaxation were hastened in AC8TG mice only. Carbachol (10 microM) had no effect on basal contractility in NTG hearts but decreased LVSP by 50% in AC8TG mice. PDE assays demonstrated an increase in cAMP-PDE activity in AC8TG hearts, mainly due to an increase in the hydrolytic activity of PDE4 and PDE1 toward cAMP and a decrease in the activity of PDE1 and PDE2 toward cGMP. We conclude that cardiac expression of AC8 is accompanied by a rearrangement of PDE isoforms, leading to a strong compartmentation of the cAMP signal that shields L-type Ca2+ channels and protects the cardiomyocytes from Ca2+ overload.
Georget
Marie
M
Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université Paris-Sud, Faculté de Pharmacie, 5, Rue J.-B. Clément, F-92296 Châtenay-Malabry Cedex, France.
Mateo
Philippe
P
Vandecasteele
Grégoire
G
Lipskaia
Larissa
L
Defer
Nicole
N
Hanoune
Jacques
J
Hoerter
Jacqueline
J
Lugnier
Claire
C
Fischmeister
Rodolphe
R
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002451:Cell Compartmentation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004553:Electric Conductivity; D015870:Gene Expression; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000502:physiology; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D018721:Muscarinic Agonists; D010726:Phosphodiesterase Inhibitors; D002217:Carbachol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine