The PDE-Opathies: Diverse Phenotypes Produced by a Functionally Related Multigene Family

The phosphodiesterase (PDE)--opathies are disorders caused by mutations in the 21-member family of human genes encoding enzymes that hydrolyze cyclic nucleotides cAMP and/or cAMP. PDEs an important and expanding set targets for drug development.The various PDE-opathies remarkably diverse, with phenotypes varying from development/neoplasia (e.g., PDE8 PDE11), to cardiovascular system (PDE3) bone formation (PDE3 PDE4), visual (PDE6), central nervous (CNS) (PDE2, PDE4, PDE10 others).The majority produced gain-of-function mutations.The PDE highly conserved among metazoans typically regulatory region(s) proteins.The provide novel insights into functional aspects structure enzymology, essential further discovery. (PDE)-opathies, germline nucleotide PDEs, present intriguing paradox. encoded all cGMP, but different members produce very divergent phenotypes. Three interacting factors have been shown recently contribute this phenotypic diversity: (i) 21 encode over 80 isoforms, using alternative mRNA splicing related mechanisms; (ii) isoforms mechanisms, mediated their unique amino-terminal domains; (iii) differ widely pattern tissue expression. These mechanisms explain why many how they exemplify uniqueness redundancy within a multigene family. (PDE)-opathies (see Glossary) defined (Figure 1). Study provides fresh insight genetic inter-relationships develop between excellent example family, as numerous distinct genes, exist cells proteins share substantial amino acid sequence homology, overlapping enzymatic activities [1.Beavo J.A. Brunton L.L. Cyclic research -- still after half century.Nat. Rev. Mol. Cell Biol. 2002; 3: 710-718Crossref PubMed Scopus (677) Google Scholar, 2.Conti M. Beavo J. Biochemistry physiology phosphodiesterases: components signaling.Annu. Biochem. 2007; 76: 481-511Crossref (905) 3.Francis S.H. et al.Mammalian molecular physiological functions.Physiol. 2011; 91: 651-690Crossref (404) 4.Maurice D.H. al.Advances targeting phosphodiesterases.Nat. Drug Discov. 2014; 13: 290-314Crossref (459) 5.Baillie G.S. al.Therapeutic 3',5'-cyclic inhibition beyond.Nat. 2019; 18: 770-796Crossref (79) 6.Bolger G.B. Phosphodiesterase – annotated list.in: Nucleotide Phosphodiesterases Health Disease. CRC Press, 2007: 19-31Google Scholar] 2). To what extent does each member role? Conversely, is there or overlap members? vary according context, disease states? can perspective these fundamental questions clarify extensive data on superfamily has generated biochemical pharmacological approaches (Box 1) [4.Maurice Scholar,5.Baillie Scholar,7.Zhang K.Y. al.A glutamine switch mechanism selectivity phosphodiesterases.Mol. Cell. 2004; 15: 279-286Abstract Full Text PDF (236) 8.Card G.L. al.Structural basis activity drugs inhibit phosphodiesterases.Structure. (Camb.). 12: 2233-2247Abstract (321) 9.Azevedo M.F. al.Clinical genetics phosphodiesterases (PDEs).Endocr. 35: 195-233Crossref (131) 10.Omar F. al.Small-molecule allosteric activators PDE4 long form AMP phosphodiesterases.Proc. Natl. Acad. Sci. U. S. A. 116: 13320-13329Crossref (26) Scholar].Figure 2Schematic representations structures 11 (PDE) families.Show full captionAll contain catalytic domain (blue) located carboxyl terminal (C-terminal) protein, binds substrate enzyme (i.e., cGMP) catalyzes its conversion GMP, respectively. (N-terminal) halves domains properties. Important include GAF domains, GAF-A GAF-B (light green light yellow, respectively) found PDE2, PDE5, PDE6, PDE10, PDE11. region PDE1 contains binding site calmodulin (Cam), calcium-binding protein. PDE3 several sites that, when phosphorylated, bind 14.3.3 proteins. Regulation ‘long’ involves dimerization, which mediated, part, two regions called upstream 1 (UCR1) UCR2. separate UCR1 UCR2) also functions. complex interactions regulation PDE6 described detail section supplemental information online.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Box 1Essential elements enzymology pharmacologyThe be divided families, preferences ability inhibited selective small-molecule inhibitors 2 Table main text). PDE3, PDE7, families 3′, 5′ cAMP-specific PDE9 cGMP-specific PDE1, PDE11 dual-specificity both cGMP. Although therefore specificities, differentiated pharmacologically, developed specific For example, PDE4-selective inhibitor roflumilast inhibits at concentration (IC50) least 100-fold lower than any other while IC50 differs less 10-fold. act, displace competitive inhibitors. Selective clinically drugs; (Daliresp), apremilast (Otezla), crisaborole (Eucresa) widespread clinical use respiratory inflammatory disorders, PDE5-selective sildenafil (Viagra) tadalafil (Cialis) erectile dysfunction pulmonary vascular disease. identification characterization PDE-selective continue objectives discovery it anticipated additional will moved use. It likely action identified; recent studies identified modulators outside act activators. All online. nucleotides, prototypical small molecule intracellular ‘second messengers’ In classical paradigm, cGMP synthesized plasma membrane, adenylyl cyclase (AC) guanylyl (GC), respectively, response extracellular stimuli then diffuse throughout cell, where interact effector regulate myriad cellular There variations paradigm: soluble forms AC subfractions. Synthesis breakdown (hydrolysis) often localized cells, producing signaling ‘compartments’, ‘pools’, ‘gradients’ tightly regulated space time. examples ‘crosstalk’ pathways. target exchange protein activated (EPAC), regulator mitogen-activated kinase (MAPK) overall process dynamic, short- long-term feedback loops adjust ‘gain’ pathways increase versatility range response. break down (hydrolyze) play roles signaling. humans, mammals most close relatives metazoans. Additional diversity promoters individual mRNA/protein gene, ultimately 100 isoforms. grouped (PDE1 through PDE11; Several more one gene; four (PDE4A, PDE4B, PDE4C, PDE4D) gene Finally, single indicated numbers; PDE4D3 PDE4D5 refer PDE4D gene. Throughout review, term italicized PDE4D), refers italics not used protein(s) gene(s).Table characteristics proteinsPDEGene namePDE nameSubstrate preferenceEssential regulationPrototypical inhibitorPDE1PDE1ACa-calmodulin-regulatedcAMP, cGMPCalcium8-mIBMX,ITI-214PDE1BCa-calmodulin-regulatedcAMP, cGMPCalciumPDE1CCa-calmodulin-regulatedcAMP, cGMPCalciumPDE2PDE2AcGMP-stimulatedcAMP, cGMPcGMPBay 60-7550PDE3PDE3AcGMP-inhibitedcAMPcGMPMilrinonePDE3BcGMP-inhibitedcAMPcGMPPDE4PDE4AcAMP-specificcAMPRolipram, roflumilast,apremilast,crisaborolePDE4BcAMP-specificcAMPPDE4CcAMP-specificcAMPPDE4DcAMP-specificcAMPPDE5PDE5AcGMP-specificcGMPsildenafilPDE6PDE6ARod cGMP-specific, alpha-subunitcGMPLightPDE6BRod beta-subunitcGMPLightPDE6CCone alpha′-subunitcGMPLightPDE7PDE7AcAMP-specific, high affinitycAMPBRL-50481,ASB16165PDE7BcAMP-specific, affinitycAMPPDE8PDE8APDE8cAMPPF-04957325PDE8BPDE8cAMPPDE9PDE9APDE9cGMPIMR-687PDE10PDE10APDE10cAMP, cGMPTAK-063,OMS824PDE11PDE11APDE11cGMP, Open table new tab date, implicated causes endocrine tumorigenesis (PDE11A PDE8B), hypertension (PDE3A), formation, such acrodysostosis brachydactyly (PDE3A affecting pathways, retinitis pigmentosa retinopathies (PDE6A, PDE6B, PDE6C), chorea striatum (PDE10A PDE2A). Each One striking extraordinary specificity affect sensory organ (the eye) exclusively, others only (CNS), proliferative/neoplastic effect limited tissues. This paradoxical, given actions two, closely related, chemical reactions hydrolysis carefully performed pharmacologic clearly distinguish 2, 1, Box 1), differences phenotype nonetheless striking. Fundamentally, paradox illuminates relationships occur Typically, partially redundant, substitute loss inactivation another bi-allelic loss-of-function complemented member). Clearly, however, relatively modest superfamily, otherwise we would seen impressive number especially wide observed. compelling explanation individualized patterns expression best tissue-specific almost exclusively retinal photoreceptor [11.McLaughlin M.E. al.Recessive beta-subunit rod patients pigmentosa.Nat. Genet. 1993; 4: 130-134Crossref (487) 12.Gal al.Heterozygous missense mutation autosomal dominant stationary night blindness.Nat. 1994; 7: 64-68Crossref (147) 13.Dryja T.P. al.Mutations alpha subunit cGMP-gated channel recessive pigmentosa.Proc. 1995; 92: 10177-10181Crossref (237) 14.Huang al.Autosomal phosphodiesterase.Nat. 11: 468-471Crossref (202) 15.McLaughlin al.Mutation spectrum beta 3249-3253Crossref (256) 16.Dryja al.Frequency cGMP-phosphodiesterase pigmentosa.Invest. Ophthalmol. Vis. 1999; 40: 1859-1865PubMed 17.Muradov K.G. linked congenital blindness impairs gamma-subunit.Biochemistry. 2003; 42: 3305-3310Crossref (29) 18.Dvir L. al.Autosomal-recessive early-onset PDE6G, gamma phosphodiesterase.Am. Hum. 2010; 87: 258-264Abstract (45) 19.Maryam al.The organization 6 (PDE6): structural implications somatic cancer pigmentosa.Comput. Struct. Biotechnol. 17: 378-389Crossref (14) 20.Weisschuh N. PDE6C cone achromatopsia.Hum. Mutat. 2018; 39: 1366-1371Crossref (11) 21.Grau T. al.Decreased altered activation properties mutants associated 20: 719-730Crossref [22.Hartong D.T. al.Retinitis pigmentosa.Lancet. 2006; 368: 1795-1809Abstract (2060) Scholar,23.Yau K.W. Hardie R.C. Phototransduction motifs variations.Cell. 2009; 139: 246-264Abstract (270) reviews). Even expressed rods cones. Additionally, membrane-targeting optimized cells. including low levels cones and, functions considerations mean little PDEs. Therefore, perhaps surprising minimal superfamily: retina, cause known spare retina. exception rule PDE6D, which, surprisingly, tissues non-retinal online details). other, non-PDE6, reflect, those express multiple unique, probably help certain cell/tissue types. effects PDE11A tumors hormone-sensitive tissues, adrenal cortex testis, may reflect requirement normal cortex, Leydig/Sertoli respectively [24.Fawcett al.Molecular cloning family: PDE11A.Proc. 2000; 97: 3702-3707Crossref (332) 25.Yuasa K. al.Isolation variants showing expression.J. Chem. 275: 31469-31479Abstract (128) 26.Yuasa al.Genomic Evolutionary relatedness containing domains.Eur. 2001; 268: 168-178Crossref 27.D'Andrea M.R. al.Expression malignant tissues.J. Histochem. Cytochem. 2005; 53: 895-903Crossref (49) 28.Boikos S.A. al.Phosphodiesterase 11A primary pigmented nodular adrenocortical disease, corticotropin-independent lesions.Horm. Metab. Res. 2008; 347-353Crossref (30) Scholar]. Similarly, PDE10A movement-related [29.Niccolini al.PDE10A ADCY5 microstructural basal ganglia pathology.Mov. Disord. 33: 1961-1965Crossref (17) Scholar,30.Diggle C.P. al.Biallelic lead striatal hyperkinetic movement disorder onset infancy.Am. 2016; 98: 735-743Abstract (39) addition, possible, fact some cases, lack tissues/cells, normally action, observed phenotype. particularly downstream targets, A (PKA) G (PKG) cells/tissues development PDE-related interaction hypertensive PDE3A complexes smooth muscle [31.Ercu 3A arterial hypertension.Circulation. 2020; 142: 133-149Crossref (7) 32.Vandeput al.Selective isoforms.Proc. 2013; 110: 19778-19783Crossref (18) 33.Ahmad al.Regulation sarcoplasmic reticulum Ca2+ ATPase (SERCA2) (PDE3A) myocardium: phosphorylation-dependent PDE3A1 SERCA2.J. 2015; 290: 6763-6776Abstract expressing complexes, As identified, certainly interest observe similarities Given overlaps reasonable predict PDE-opathy would, another. concept, essentially converse discussed previous section, follows concept redundant mutated, good skeletal/bone Scholar,34.Maass P.G. al.PDE3A brachydactyly.Nat. 47: 647-653Crossref (100) 35.Boda H. familial syndrome.J. 61: 701-703Crossref (27) 36.Toka O. inherited brachydactyly.Hypertension. 66: 800-808Crossref 37.Lee al.Exome sequencing identifies acrodysostosis.Am. 2012; 90: 746-751Abstract (106) 38.Michot C. 740-745Abstract (102) 39.Linglart al.PRKAR1A syndromes without GPCR-signaling hormone resistance.J. Clin. Endocrinol. E2328-E2338Crossref (85) 40.Muhn al.Novel PRKAR1A acrodysostosis.Clin. 84: 531-538Crossref (24) 41.Elli F.M. al.Screening large Italian series diagnosed Albright hereditary osteodystrophy pseudohypoparathyroidism.J. Bone Miner. 31: 1215-1224Crossref (41) 42.Briet causing acrodysostosis-2 facilitate 4D3.Hum.