Compartmentalized Phosphodiesterase-2 Activity Blunts &bgr;-Adrenergic Cardiac Inotropy via an NO/cGMP-Dependent Pathway

&bgr;-Adrenergic signaling via cAMP generation and PKA activation mediates the positive inotropic effect of catecholamines on heart cells. Given the large diversity of protein kinase A targets within cardiac cells, a precisely regulated and confined activity of such signaling pathway is essential for specificity of response. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP]i in a stimulus-specific manner. By performing real-time imaging of cyclic nucleotides in living ventriculocytes we identify a prominent role of PDE2 in selectively shaping the cAMP response to catecholamines via a pathway involving &bgr;3-adrenergic receptors, NO generation and cGMP production. In cardiac myocytes, PDE2, being tightly coupled to the pool of adenylyl cyclases activated by &bgr;-adrenergic receptor stimulation, coordinates cGMP and cAMP signaling in a novel feedback control loop of the &bgr;-adrenergic pathway. In this, activation of &bgr;3-adrenergic receptors counteracts cAMP generation obtained via stimulation of &bgr;1/&bgr;2-adrenoceptors. Our study illustrates the key role of compartmentalized PDE2 in the control of catecholamine-generated cAMP and furthers our understanding of localized cAMP signaling.

[1]  D. Kass,et al.  Calcitonin Gene-Related Peptide In Vivo Positive Inotropy Is Attributable to Regional Sympatho-Stimulation and Is Blunted in Congestive Heart Failure , 2005, Circulation research.

[2]  M. Zaccolo,et al.  cGMP Catabolism by Phosphodiesterase 5A Regulates Cardiac Adrenergic Stimulation by NOS3-Dependent Mechanism , 2004, Circulation research.

[3]  M. Zaccolo,et al.  Study of cyclic adenosine monophosphate microdomains in cells. , 2005, Methods in molecular biology.

[4]  D. Cooper,et al.  Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes , 2004, Journal of Biological Chemistry.

[5]  Martin J. Lohse,et al.  Fluorescence Resonance Energy Transfer–Based Analysis of cAMP Dynamics in Live Neonatal Rat Cardiac Myocytes Reveals Distinct Functions of Compartmentalized Phosphodiesterases , 2004, Circulation research.

[6]  P. Insel,et al.  Nitric Oxide Inhibition of Adenylyl Cyclase Type 6 Activity Is Dependent upon Lipid Rafts and Caveolin Signaling Complexes* , 2004, Journal of Biological Chemistry.

[7]  M. Zaccolo,et al.  Use of Chimeric Fluorescent Proteins and Fluorescence Resonance Energy Transfer to Monitor Cellular Responses , 2004, Circulation research.

[8]  D. Cooper,et al.  Negative Feedback Exerted by PKA and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes , 2004 .

[9]  E. Aandahl,et al.  Localized effects of cAMP mediated by distinct routes of protein kinase A. , 2004, Physiological reviews.

[10]  M. Houslay,et al.  PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. , 2003, The Biochemical journal.

[11]  S. Maekawa,et al.  Localization of cyclic nucleotide phosphodiesterase 2 in the brain-derived Triton-insoluble low-density fraction (raft) , 2003, Neuroscience Research.

[12]  R. Lefkowitz,et al.  Retraction for Baillie et al., β-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates β-adrenoceptor switching from Gs to Gi , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  K. Omori,et al.  cGMP-Phosphodiesterase Activity Is Up-regulated in Response to Pressure Overload of Rat Ventricles , 2003, Bioscience, biotechnology, and biochemistry.

[14]  R. Lefkowitz,et al.  beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  W. Hol,et al.  GAF domains: two-billion-year-old molecular switches that bind cyclic nucleotides. , 2002, Molecular interventions.

[16]  J. Beavo,et al.  Cyclic nucleotide research — still expanding after half a century , 2002, Nature Reviews Molecular Cell Biology.

[17]  M. Kapiloff.  Contributions of protein kinase A anchoring proteins to compartmentation of cAMP signaling in the heart. , 2002, Molecular pharmacology.

[18]  U. Ravens,et al.  Physiological antagonism between ventricular β1‐adrenoceptors and α1‐adrenoceptors but no evidence for β2‐ and β3‐adrenoceptor function in murine heart , 2002 .

[19]  M. Zaccolo,et al.  Compartmentalisation of cAMP and Ca(2+) signals. , 2002, Current opinion in cell biology.

[20]  Tullio Pozzan,et al.  Discrete Microdomains with High Concentration of cAMP in Stimulated Rat Neonatal Cardiac Myocytes , 2002, Science.

[21]  U. Ravens,et al.  Physiological antagonism between ventricular beta 1-adrenoceptors and alpha 1-adrenoceptors but no evidence for beta 2- and beta 3-adrenoceptor function in murine heart. , 2002, British journal of pharmacology.

[22]  Joao A. C. Lima,et al.  Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms , 2002, Nature.

[23]  T. Kohout,et al.  Augmentation of Cardiac Contractility Mediated by the Human &bgr;3-Adrenergic Receptor Overexpressed in the Hearts of Transgenic Mice , 2001, Circulation.

[24]  A. Kamkin,et al.  Inotropic response to β‐adrenergic receptor stimulation and anti‐adrenergic effect of ACh in endothelial NO synthase‐deficient mouse hearts , 2001, The Journal of physiology.

[25]  J. Balligand,et al.  Upregulation of &bgr;3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium , 2001, Circulation.

[26]  Roger Y. Tsien,et al.  Spatiotemporal dynamics of guanosine 3′,5′-cyclic monophosphate revealed by a genetically encoded, fluorescent indicator , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Lisanti,et al.  Differential targeting of beta -adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae. A mechanism to functionally regulate the cAMP signaling pathway. , 2000, The Journal of biological chemistry.

[28]  D. Kass,et al.  cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation. , 2000, American journal of physiology. Heart and circulatory physiology.

[29]  E. Degerman,et al.  Cyclic Nucleotide Phosphodiesterases (PDEs): Diverse Regulators of Cyclic Nucleotide Signals and Inviting Molecular Targets for Novel Therapeutic Agents , 1999, Thrombosis and Haemostasis.

[30]  M. Colledge,et al.  AKAPs: from structure to function. , 1999, Trends in cell biology.

[31]  L. Luttrell,et al.  The β3-Adrenergic Receptor Activates Mitogen-activated Protein Kinase in Adipocytes through a Gi-dependent Mechanism* , 1999, The Journal of Biological Chemistry.

[32]  R. Fischmeister,et al.  Muscarinic and beta-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. , 1999, Nature medicine.

[33]  Susan S. Taylor,et al.  A genetically encoded, fluorescent indicator for cyclic AMP in living cells , 1999, Nature Cell Biology.

[34]  J. Balligand,et al.  The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. , 1998, The Journal of clinical investigation.

[35]  G. Milligan,et al.  Tailoring cAMP-signalling responses through isoform multiplicity. , 1997, Trends in biochemical sciences.

[36]  R. Fischmeister,et al.  cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. , 1997, The Journal of clinical investigation.

[37]  H. S. Kim,et al.  Elevated blood pressures in mice lacking endothelial nitric oxide synthase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Balligand,et al.  Nitric oxide synthase (NOS3)-mediated cholinergic modulation of Ca2+ current in adult rabbit atrioventricular nodal cells. , 1996, Circulation research.

[39]  E. Ongini,et al.  The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2a adenosine receptor antagonist. , 1996, The Journal of pharmacology and experimental therapeutics.

[40]  M. Houslay,et al.  Rapid regulation of PDE-2 and PDE-4 cyclic AMP phosphodiesterase activity following ligation of the T cell antigen receptor on thymocytes: analysis using the selective inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) and rolipram. , 1996, Cellular signalling.

[41]  R Fischmeister,et al.  cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Houslay,et al.  Identification, characterization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. , 1995, The Biochemical journal.

[43]  W. Giles,et al.  A cellular mechanism for nitric oxide-mediated cholinergic control of mammalian heart rate , 1995, The Journal of general physiology.

[44]  R Marsault,et al.  Transfected Aequorin in the Measurement of Cytosolic Ca2+ Concentration ([Ca2+]c) , 1995, The Journal of Biological Chemistry.

[45]  R Fischmeister,et al.  Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. , 1993, The Journal of biological chemistry.

[46]  O. Brodde.  Beta-adrenoceptors in cardiac disease. , 1993, Pharmacology & therapeutics.

[47]  K. Rothblum,et al.  Detection of angiotensin I and II in cultured rat cardiac myocytes and fibroblasts. , 1992, The American journal of physiology.

[48]  S. Liggett,et al.  Long-term agonist exposure induces upregulation of beta 3-adrenergic receptor expression via multiple cAMP response elements. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[49]  R Fischmeister,et al.  Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[50]  E. Lakatta,et al.  Single adult rabbit and rat cardiac myocytes retain the Ca2+- and species-dependent systolic and diastolic contractile properties of intact muscle , 1986, The Journal of general physiology.

[51]  M. Houslay,et al.  Identification and characterization of both the cytosolic and particulate forms of cyclic GMP-stimulated cyclic AMP phosphodiesterase from rat liver. , 1986, The Biochemical journal.

[52]  L. Brunton,et al.  Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes. , 1983, The Journal of biological chemistry.

[53]  M. Houslay,et al.  A peripheral and an intrinsic enzyme constitute the cyclic AMP phosphodiesterase activity of rat liver plasma membranes. , 1980, The Biochemical journal.

[54]  G L MADDOX,et al.  A critical evaluation , 2012 .