Phosphodiesterases

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Phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) cAMP signaling operating in such cells. catalyze the hydrolysis of cAMP and/or cGMP. For various PDEs, located immediately N- They function with adenylyl and guanylyl terminal to the catalytic unit are family-specific cyclases to regulate the amplitude and duration paired regulatory domains. These allow of responses triggered by the second regulation through cross-talk with various other messengers, cAMP and cGMP. In doing so they signal transduction systems by either regulate a wide range of biological responses phosphorylation or allosteric regulation. triggered by light, hormones, neurotransmitters and odorants. Two classes of functional PDEs, PDEs are named to identify isoforms. Thus, which do not share any sequence homology, are HSPDE4A1 refers to the Homo sapiens PDE4 recognized: Class I PDEs, found in all eukaryotic family, gene A, splice variant 1. The high level of cells and Class II PDEs, found in lower sequence conservation among species, distinct eukaryotes. intracellular targeting and kinetic and regulatory There are 11 different mammalian PDE families characteristics suggest that individual PDEs play of which PDE4, PDE7 and PDE8 are specific for particular roles in specific physiological cAMP, while PDE5, PDE6 and PDE9 are specific processes. For example, PDE1 isoforms have for cGMP and others hydrolyze both cAMP and twin regulatory domains that allow them to bind cGMP. PDE3, whose Vmax cAMP > Vmax cGMP and be activated by Ca2+/calmodulin, providing and Km cGMP < Km cAMP, is generally cross talk between the Ca2+ and cAMP/cGMP considered as a cGMP-inhibited cAMP signaling pathways. They can participate in the hydrolyzing PDE. feed-forward amplification of neuronal signals. PDEs contain a conserved, catalytic domain of PDE2 has twin regulatory GAF domains that around 250 amino acids, where an invariant allow binding and activation by cGMP, providing glutamine provides the key specificity cross talk with the cGMP/NO signaling pathway. determinant by scanning the purine moiety in Indeed, PDE2A plays a role in regulating cAMP/cGMP. Adjacent residues anchor this aldosterone production in adrenal glomerulosa glutamine in different orientations so as to define cells through integration of cAMP and cGMP specificity for either or both cAMP/cGMP. signals. PDE3, which hydrolyzes cAMP, has a unique insert in its catalytic region, which Twenty-one genes encode the 11 known PDE attenuates its cGMP hydrolyzising capacity such families with additional isoform diversity that cGMP potently inhibits cAMP hydrolysis by generated through alternative mRNA splicing and this enzyme. This allows elevation of cGMP to the use of distinct promoters. Isoforms have an potentiate cAMP signals, which has functional extreme N-terminal domain that uniquely significance in regulation of platelet aggregation. characterizes them. In various PDE families, and PDE3B underpins the anti-lipolytic action of particularly with PDE4, this is involved in insulin in adipocytes through being intracellular targeting. Different cell types express phosphorylated and activated by PKB/Akt. PDE3, a unique complement of PDE isoforms, thereby together with PDE4 isoforms, provide the major individually tailoring the nature of the spatial and cAMP hydrolyzing activity in many cells. PDE4 kinetic characteristics of the cAMP signal. This isoforms underpin much of compartmentalized defines the characteristics of compartmentalized cAMP signaling by interacting with a range

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of scaffold proteins, including barrestin, AKAPs, modulation of cGMP hydrolysis subsequent to SRC, kinases, myomegalin and RACK1. Their activation by GTP-bound transducin. The phosphorylation by ERK configures cross-talk functional significance of the newer PDEs is not with this pathway and phosphorylation by PKA well appreciated and they provide a challenge for promotes cAMP desensitization. Chemical and the future in understanding their physiological genetic knockout identifies PDE4s as having a roles. key role in inflammatory responses, memory and depression. PDE5, has cGMP-binding, regulatory The Table below contains accepted modulators GAF domains and plays a role in regulating and additional information. For more information smooth muscle tension in certain vascular beds. and a complete list of the related products, please Sildenafil, a selective PDE5A inhibitor, is used to click: Aladdin treat erectile dysfunction. PDE6 plays a central role in visual phototransduction through rapid

Family Name PDE1 PDE2 PDE3 PDE4 PDE5

Known 1A, 1B, 1C 2A 3A, 3B 4A, 4B, 4C, 4D 5A Genes

Descriptive CaM-dependent PDE cGMP- cGMP-inhibited cAMP-specific PDE cGMP-binding Name stimulated PDE PDE PDE

1141 aa Structural 535 aa (human) 941 aa (human) 647 aa (human) 874 aa (human) (human) Information HSPDE1A3 HSPDE2A3 HSPDE4A1 HSPDE5A1 HSPDE3A1

cGMP PKA Regulators Ca2+/CaM Insulin ERK PKG Leptin , Phosphatidic acid

Substrate cAMP or cAMP or cAMP or cAMP cGMP Specificity cGMP cGMP cGMP

*Cilostamide *Sildenafi Enoximone *Rolipram *Vardenafil Vinpocetine *EHNA Inhibitors Imazodan *Ro20-1724 Dipyridamole SCH-51866 *BAY60-7550 Trequinsin *RP 73401 T-1032 Milrinone Zaprinast

Heart Lung Adrenal cortex Major Tissue Brain, heart, smooth Adipose Platelets Brain Many tissues Expression muscle, olfactory cilia Pancreas Smooth muscle Heart Platelets Corpus collusum

Regulates monocyte, macrophage T-cell, eosinophil, neutrophil function Sperm development Regulates neuronal function and maturation β2/β3 regulation and differentiation Monocyte/macrophage of cardiac Platelet function Vascular smooth Physiological Regulates functions of differentiation myocytes Adipocyte muscle cell Function inflammatory cells and Olfactory neuron Endothelial cell function relaxation vascular smooth muscle cells regulation function Pro-apoptotic Neuronal regulation Anti-apoptotic Endothelial cell function Inhibition of bone loss

Intermittent Airway inflammation (asthma, Penile erectile claudication COPD) dysfunction Fertility peripheral Rheumatoid arthritis Disease Heart disease Asthma Inflammation arterial occlusive Crohn's disease Relevance Anti-angiogenic COPD Olfaction disease Learning Pulmonary Restenosis Memory hypertension Obesity Schizophrenia

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Type-2 diabetes Spinal cord injury Migraine Stroke Restenosis Chronic B-cell lymphocytic leukemia Spinal cord injury Parkinson's Disease Anti-angiogenic Osteopenia (including osteoporosis)

Family Name PDE6 PDE7 PDE8 PDE9 PDE10 PDE11

Known Genesa 6A, 6B 7A, 7B 8A, 8B 9A 10A 11A

High affinity High affinity Descriptive Photoreceptor cAMP- Dual specificity Dual specificity cAMP- cGMP- Name PDE specific PDE PDE PDE specific PDE specific PDE

Structural 860 aa (human) 482 aa (human) 713 aa (human) 593 aa (human) 779 aa (human) 490 aa (human) Informationb HSPDE6A1 HSPDE7A1 HSPDE8A1 HSPDE9A1 HSDPE10A1 HSPDE11A1

Regulators Light Not Known Not Known Not Known PKA Not Known

Substrate cAMP or cAMPor cGMP cAMP cAMP cGMP Specificity cGMP cGMP

SCH-51866d c Zaprinast d Zaprinast Inhibitors BRL50481 Dipyridamole SCH-51866 Zaprinast Dipyridamole Dipyridamole Dipyridamole

Rod and cone Testis Major Tissue Skeletal muscle Testis Skeletal muscle Photoreceptor Liver Kidney Expression T-cells Brain Prostate Outer segments Thyroid

Sperm function Physiological Visual signal Thyroid function Striatal neuron Not Known Not Known (motility, Function transduction T-cell activation function number)

Parkinsonism Schizophrenia Hyperthyroidism Disease Retinitis Obsessive Metabolic bone Fertility Fertility Relevance pigmentosa compulsive disease disorders Addictions

Abbreviations trimethoxyphenyl)-3-isoquinoline carboxylate CaM: Calmodulin sulfate EHNA: Erythro-9-(2-hydroxy-3-nonyl)adenine PKA: cAMP-dependent protein kinase b: bovine PKG: cGMP-dependent protein kinase h: human Ro 20-1724: 4-[(3-Butoxy-4- m: mouse methoxyphenyl)methyl]2-imidazolidinone r: rat RP 73401: N-(3,5-Dichloropyrid-4-yl)-3- cyclopentyloxy-4-methoxybenzamide References SB-207499: c-4-Cyano-4-(3-cyclopentyloxy-4- Baillie, G.S., et al., beta-Arrestin-mediated PDE4 methoxyphenyl-r-1-cyclohexane carboxylic acid) cAMP phosphodiesterase recruitment regulates SCH-51866: cis-5,6a,7,8,9,9a-Hehahydro-2-[4- beta-adrenoceptor switching from Gs to Gi., Proc (trifluoromethyl)phenylmethyl]-5-methyl- Natl. Acad. Sci. USA, 100, 940-945 (2003). cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one Beavo, J.A. and Brunton, L.L., Cyclic nucleotide T-1032: Methyl-2-(4-aminophenyl)-1,2-dihydro-1- research - still expanding after half a century., oxo-7-(2-pyridinylmethoxy)-4-(3,4,5- Nat. Rev. Mol. Cell Biol., 3, 710-718 (2002).

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Conti, M., et al., Cyclic AMP-specific PDE4 Acad. Sci. USA, 99, 13260-13265 (2002). phosphodiesterases as critical components of Masciarelli, S., et al., Cyclic nucleotide cyclic AMP signaling., J. Biol. Chem., 278, 5493- phosphodiesterase 3A-deficient mice as a model 5496 (2003). of female infertility., J. Clin. Invest., 114, 196-205 Francis, S.H., et al., Cyclic nucleotide (2004). phosphodiesterases: relating structure and Maurice, D.H., et al., Cyclic nucleotide function., Prog. Nucleic Acid Res. Mol. Biol., 65, phosphodiesterase activity, expression, and 1-52 (2001). targeting in cells of the cardiovascular system., Gresele, P., et al., Anti-platelet therapy: Mol. Pharmacol., 64, 533-546 (2003). phosphodiesterase inhibitors., Br J Clin Mongillo, M., et al., Fluorescence resonance Pharmacol., 72, 634-646 (2011). energy transfer-based analysis of cAMP Houslay, M.D. and Adams, D.R., PDE4 cAMP dynamics in live neonatal rat cardiac myocytes phosphodiesterases: modular enzymes that reveals distinct functions of compartmentalized orchestrate signaling cross-talk, desensitization phosphodiesterases., Circ. Res., 95, 67-75 and compartmentalization., Biochem J., 370, 1- (2004). 18 (2003). O'Donnell, J.M. and Zhang, H.T., Antidepressant Huai, Q., et al., Three-dimensional structures of effects of inhibitors of cAMP phosphodiesterase PDE4D in complex with roliprams and implication (PDE4)., Trends Pharmacol. Sci., 25, 158-163 on inhibitor selectivity., Structure (Camb), 11, (2004). 865-873 (2003). Page, CP. and Spina, D., Selective PDE Keravis, T. and Lugnier, C., Cyclic nucleotide inhibitors as novel treatments for respiratory phosphodiesterase (PDE) isozymes as targets of diseases., Curr Opin Pharmacol., 12, 275-286 the intracellular signalling network: benefits of (2012). PDE inhibitors in various diseases and Schwartz, BG., et al., Phosphodiesterase type 5 perspectives for future therapeutic inhibitors improve endothelial function and may developments., Br J Pharmacol., 165, 1288-1305 benefit cardiovascular conditions., Am J Med., (2012). 126, 192-199 (2013). Levy, I., et al., Phosphodiesterase function and Zhang, K.Y., et al., A glutamine switch endocrine cells: links to human disease and roles mechanism for nucleotide selectivity by in tumor development and treatment., Curr Opin phosphodiesterases., Mol Cell, 15, 279-286 Pharmacol., 11, 689-697 (2011). (2004). Martinez, S.E., et al., The two GAF domains in phosphodiesterase 2A have distinct roles in For more information and a complete list of the dimerization and in cGMP binding., Proc. Natl. related products, please click: Aladdin

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