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W2034832260 abstract "cGKs 1The abbreviations used are: cGK, cGMP-dependent protein kinase; [Ca2+]i, intracellular Ca2+ concentration; 8-Br-cGMP, 8-bromo-cGMP; IP3, inositol 1,4,5-trisphosphate; MLCK, myosin light chain kinase; RLC, regulatory myosin light chain; MLCP, myosin light chain phosphatase; IRAG, IP3 receptor-associated cGKI substrate; MBS, myosin-binding subunit; MYPT, myosin/phosphatase-targeting subunit; VASP, vasodilator-stimulated phosphoprotein; STa, heat-stable enterotoxin of Escherichia coli; SCN, suprachiasmatic nucleus. belong to the family of serine/threonine kinases and are present in a variety of eukaryotes ranging from the unicellular organism Paramecium to Homo sapiens (1Pfeifer A. Ruth P. Dostmann W. Sausbier M. Klatt P. Hofmann F. Rev. Physiol. Biochem. Pharmacol. 1999; 135: 105-149Crossref PubMed Google Scholar, 2Francis S.H. Corbin J.D. Crit. Rev. Clin. Lab. Sci. 1999; 36: 275-328Crossref PubMed Scopus (261) Google Scholar). Mammals have two cGK genes, prkg1 and prkg2, that encode cGKI and cGKII. The N terminus (the first 90-100 residues) of cGKI is encoded by two alternatively spliced exons that produce the isoforms cGKIα and cGKIβ. The enzymes have a rod-like structure and are activated at submicromolar to micromolar concentrations of cGMP (3Ruth P. Pfeifer A. Kamm S. Klatt P. Dostmann W.R. Hofmann F. J. Biol. Chem. 1997; 272: 10522-10528Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 4Gamm D.M. Francis S.H. Angelotti T.P. Corbin J.D. Uhler M.D. J. Biol. Chem. 1995; 270: 27380-27388Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). They are composed of three functional domains: an N-terminal (A) domain, a regulatory (R) domain, and a catalytic (C) domain (for details see Refs. 1Pfeifer A. Ruth P. Dostmann W. Sausbier M. Klatt P. Hofmann F. Rev. Physiol. Biochem. Pharmacol. 1999; 135: 105-149Crossref PubMed Google Scholar and 2Francis S.H. Corbin J.D. Crit. Rev. Clin. Lab. Sci. 1999; 36: 275-328Crossref PubMed Scopus (261) Google Scholar). The regulatory domain contains two tandem cGMP-binding sites that interact allosterically and bind cGMP with high and low affinity. Occupation of both binding sites induces a large change in secondary structure (5Landgraf W. Hofmann F. Pelton J.T. Huggins J.P. Biochemistry. 1990; 29: 9921-9928Crossref PubMed Scopus (35) Google Scholar) to yield a more elongated molecule (6Zhao J. Trewhella J. Corbin J. Francis S. Mitchell R. Brushia R. Walsh D. J. Biol. Chem. 1997; 272: 31929-31936Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 7Wall M.E. Francis S.H. Corbin J.D. Grimes K. Richie-Jannetta R. Kotera J. Macdonald B.A. Gibson R.R. Trewhella J. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 2380-2385Crossref PubMed Scopus (61) Google Scholar). The catalytic domain contains the MgATP- and peptide-binding pockets. Binding of cGMP to both sites in the R domain releases the inhibition of the catalytic center by the N-terminal autoinhibitory/pseudosubstrate site and allows the phosphorylation of serine/threonine residues in target proteins and in the N-terminal autophosphorylation site. Activation of heterophosphorylation may be preceded by autophosphorylation. Autophosphorylation increases the spontaneous activity of cGKI and cGKII (8Smith J.A. Francis S.H. Walsh K.A. Kumar S. Corbin J.D. J. Biol. Chem. 1996; 271: 20756-20762Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 9Wyatt T.A. Lincoln T.M. Pryzwansky K.B. J. Biol. Chem. 1991; 266: 21274-21280Abstract Full Text PDF PubMed Google Scholar, 10Vaandrager A.B. Hogema B.M. van den Edixhoven M. Burg C.M. Bot A.G. Klatt P. Ruth P. Hofmann F. Van Damme J. Vandekerckhove J. de Jonge H.R. J. Biol. Chem. 2003; 278: 28651-28658Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 11Francis S.H. Poteet-Smith C. Busch J.L. Richie-Jannetta R. Corbin J.D. Front Biosci. 2002; 7: d580-d592Crossref PubMed Google Scholar) and is initiated by the binding of low cGMP concentrations to the high affinity site of cGKI (12Hofmann F. Gensheimer H.P. Gobel C. Eur. J. Biochem. 1985; 147: 361-365Crossref PubMed Scopus (52) Google Scholar, 13Smith J.A. Reed R.B. Francis S.H. Grimes K. Corbin J.D. J. Biol. Chem. 2000; 275: 154-158Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). In addition to controlling activation and inhibition of the catalytic center, the N terminus has two other functions: dimerization, cGKs are homodimers that are held together by a leucine zipper present in the N terminus, and targeting, the enzymes are targeted to different subcellular localizations by their N termini. cGKI is present in high concentrations (>0.1 μm) in all smooth muscles, platelets, cerebellum, hippocampus, dorsal root ganglia, neuromuscular endplate, and kidney. Low levels have been identified in cardiac muscle, vascular endothelium, granulocytes, chondrocytes, and osteoclasts. The Iα isozyme is found in lung, heart, dorsal root ganglia, and cerebellum. Together with the Iα isozyme, the Iβ isozyme is highly expressed in smooth muscle, including uterus, vessels, intestine, and trachea (14Geiselhoringer A. Gaisa M. Hofmann F. Schlossmann J. FEBS Lett. 2004; 575: 19-22Crossref PubMed Scopus (81) Google Scholar). Platelets, hippocampal neurons, and olfactory bulb neurons contain mainly the Iβ isozyme (14Geiselhoringer A. Gaisa M. Hofmann F. Schlossmann J. FEBS Lett. 2004; 575: 19-22Crossref PubMed Scopus (81) Google Scholar). The Iα and Iβ cGKs are soluble enzymes and interact with different proteins through their distinct N termini. cGKII is expressed in several brain nuclei, intestinal mucosa, kidney, adrenal cortex, chondrocytes, and lung (15el-Husseini A.E. Bladen C. Vincent S.R. J. Neurochem. 1995; 64: 2814-2817Crossref PubMed Scopus (87) Google Scholar, 16Lohmann S.M. Vaandrager A.B. Smolenski A. Walter U. De Jonge H.R. Trends Biochem. Sci. 1997; 22: 307-312Abstract Full Text PDF PubMed Scopus (352) Google Scholar, 17de Vente J. Asan E. Markerink-van Gambaryan S. Ittersum M. Axer H. Gallatz K. Lohmann S.M. Palkovits M. Neuroscience. 2001; 108: 27-49Crossref PubMed Scopus (68) Google Scholar, 18Werner C. Raivich G. Cowen M. Stekalowa T. Sillaber I. Buters J.T. Spanagel R. Hofmann F. Eur. J. Neurosci. 2004; (in press)Google Scholar). cGKII is anchored at the plasma membrane by myristoylation of the N-terminal Gly-2 residue. Only the membrane-bound cGKII phosphorylates cystic fibrosis transmembrane conductance regulator (19Vaandrager A.B. Smolenski A. Tilly B.C. Houtsmuller A.B. Ehlert E.M. Bot A.G. Edixhoven M. Boomaars W.E. Lohmann S.M. de Jonge H.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1466-1471Crossref PubMed Scopus (145) Google Scholar). Control of Smooth Muscle Tone by cGKI—NO and other NO-generating organic nitrates stimulate the soluble guanylyl cyclase, increase cGMP levels, and thereby relax vascular and other smooth muscles. The relaxing effect of these compounds involves the activation of cGKI as shown by deleting the cGKI gene in mice (20Pfeifer A. Klatt P. Massberg S. Ny L. Sausbier M. Hirneiss C. Wang G.X. Korth M. Aszodi A. Andersson K.E. Krombach F. Mayerhofer A. Ruth P. Fassler R. Hofmann F. EMBO J. 1998; 17: 3045-3051Crossref PubMed Scopus (455) Google Scholar). cGKI-deficient mice are hypertensive at 4 weeks but normotensive at an older age (20Pfeifer A. Klatt P. Massberg S. Ny L. Sausbier M. Hirneiss C. Wang G.X. Korth M. Aszodi A. Andersson K.E. Krombach F. Mayerhofer A. Ruth P. Fassler R. Hofmann F. EMBO J. 1998; 17: 3045-3051Crossref PubMed Scopus (455) Google Scholar, 21Koeppen M. Feil R. Siegl D. Feil S. Hofmann F. Pohl U. de Wit C. Hypertension. 2004; 44: 952-955Crossref PubMed Scopus (64) Google Scholar). The blood pressure-lowering effect of intraarterial infusion of sodium nitroprusside is abolished in cGKI-deficient mice whereas acetylcholine infusion still lowers the blood pressure (21Koeppen M. Feil R. Siegl D. Feil S. Hofmann F. Pohl U. de Wit C. Hypertension. 2004; 44: 952-955Crossref PubMed Scopus (64) Google Scholar) suggesting that cGKI is involved in the control of vascular tone but that additional mechanisms exist. Precontracted smooth muscle strips or pressurized vessels of cGKI-deficient mice are not relaxed by acetylcholine or NO (20Pfeifer A. Klatt P. Massberg S. Ny L. Sausbier M. Hirneiss C. Wang G.X. Korth M. Aszodi A. Andersson K.E. Krombach F. Mayerhofer A. Ruth P. Fassler R. Hofmann F. EMBO J. 1998; 17: 3045-3051Crossref PubMed Scopus (455) Google Scholar, 22Sausbier M. Schubert R. Voigt V. Hirneiss C. Pfeifer A. Korth M. Kleppisch T. Ruth P. Hofmann F. Circ. Res. 2000; 87: 825-830Crossref PubMed Scopus (206) Google Scholar). The defective regulation of smooth muscle tone is not confined to vascular smooth muscle but is also found in other organs. In the gastrointestinal tract, accommodation of food and generation of peristaltic waves are controlled by nonadrenergic-noncholinergic neurons, which release NO upon stimulation and relax the intestinal smooth muscle. Deletion of the cGKI gene leads to pylorus stenosis, causing severe distention of the stomach and irregular peristaltic waves that heavily retard passage of intestinal content. Deletion of cGKI did not affect cAMP-induced relaxation of vascular or intestinal smooth muscle supporting the conclusion that cAMP and cGMP use different signal pathways in smooth muscle. Smooth muscle tone is regulated by the rise and fall of [Ca2+]i. Contraction is initiated by receptor-mediated generation of IP3 that releases Ca2+ from intracellular stores followed by an influx of extracellular Ca2+ through voltage-dependent Ca2+ channels (23Moosmang S. Schulla V. Welling A. Feil R. Feil S. Wegener J.W. Hofmann F. Klugbauer N. EMBO J. 2003; 22: 6027-6034Crossref PubMed Scopus (248) Google Scholar, 24Wegener J.W. Schulla V. Lee T.S. Koller A. Feil S. Feil R. Kleppisch T. Klugbauer N. Moosmang S. Welling A. Hofmann F. Faseb. J. 2004; 18: 1159-1161Crossref PubMed Scopus (93) Google Scholar). The rise in [Ca2+]i initiates contraction by activation of the Ca2+/calmodulin-dependent MLCK, which phosphorylates RLC and, consequently, activates myosin ATPase. A decrease in [Ca2+]i inactivates MLCK and induces dephosphorylation of RLC by MLCP. Smooth muscle contraction is modulated also at constant [Ca2+]i by changing the sensitivity of contraction to [Ca2+] (25Somlyo A.P. Somlyo A.V. Physiol. Rev. 2003; 83: 1325-1358Crossref PubMed Scopus (1696) Google Scholar). cGKI interferes both with the increase in [Ca2+]i and with the Ca2+ sensitivity at several levels (Fig. 1). Some evidence indicates that cGKIα inhibits the generation of IP3 in smooth muscle and Chinese hamster ovary cells (26Ruth P. Wang G.X. Boekhoff I. May B. Pfeifer A. Penner R. Korth M. Breer H. Hofmann F. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 2623-2627Crossref PubMed Scopus (107) Google Scholar) by interfering with the inactivation of Gαq (27Tang M.K. Wang G.R. Lu P. Karas R.H. Aronovitz M. Heximer S.P. Kaltenbronn K.M. Blumer K.J. Siderovski D.P. Zhu Y. Mendelsohn M.E. Nat. Med. 2003; 9: 1506-1512Crossref PubMed Scopus (319) Google Scholar) or the activation of phospholipase Cβ3 (28Xia C. Bao Z. Yue C. Sanborn B.M. Liu M. J. Biol. Chem. 2001; 276: 19770-19777Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). However, the biological significance of these findings remains unclear because a direct correlation between the cGMP-dependent phosphorylation of a target protein and decreased IP3 synthesis has not been established. The IP3 receptor type 1 has two splice variants, the long neuronal S2+ form and the peripheral short S2- form that is expressed in smooth muscle. Both splice forms are phosphorylated in vitro and in vivo at two serines by cAMP kinase and cGKI. cGKI phosphorylates preferentially Ser-1755 (29Komalavilas P. Lincoln T.M. J. Biol. Chem. 1994; 269: 8701-8707Abstract Full Text PDF PubMed Google Scholar). Initial experiments suggested that phosphorylation of the IP3 receptor I resulted in a decreased release of Ca2+ from intracellular stores. Later experiments clearly showed that cAMP-dependent phosphorylation of each receptor isoform resulted in an increased Ca2+ release (30Wagner II, L.E. Li W.H. Yule D.I. J. Biol. Chem. 2003; 278: 45811-45817Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). cGMP-dependent phosphorylation of the peripheral IP3 receptor type I S2- isoform had no effect on Ca2+ release, whereas it increased Ca2+ release from the neuronal S2+ isoform (30Wagner II, L.E. Li W.H. Yule D.I. J. Biol. Chem. 2003; 278: 45811-45817Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). These findings suggest that cGMP-dependent phosphorylation of the IP3 receptor is not relevant for smooth muscle tone regulation but may be important for neurons that express cGKI but not IP3receptor-associated cGKI substrate (IRAG) (14Geiselhoringer A. Gaisa M. Hofmann F. Schlossmann J. FEBS Lett. 2004; 575: 19-22Crossref PubMed Scopus (81) Google Scholar). The smooth muscle IP3 receptor type 1 coprecipitates with cGKIβ and a 125-135-kDa protein identified as IRAG (31Schlossmann J. Ammendola A. Ashman K. Zong X. Huber A. Neubauer G. Wang G.X. Allescher H.D. Korth M. Wilm M. Hofmann F. Ruth P. Nature. 2000; 404: 197-201Crossref PubMed Scopus (386) Google Scholar). IRAG is expressed together with cGKIβ in smooth muscle, platelets, and some neurons (14Geiselhoringer A. Gaisa M. Hofmann F. Schlossmann J. FEBS Lett. 2004; 575: 19-22Crossref PubMed Scopus (81) Google Scholar). It is located at the endoplasmic reticulum membrane and is preferentially phosphorylated by cGKIβ at Ser-683 and Ser-696 (bovine sequence) (32Geiselhoringer A. Werner M. Sigl K. Smital P. Worner R. Acheo L. Stieber J. Weinmeister P. Feil R. Feil S. Wegener J. Hofmann F. Schlossmann J. EMBO J. 2004; 23: 4222-4231Crossref PubMed Scopus (84) Google Scholar, 33Ammendola A. Geiselhoringer A. Hofmann F. Schlossmann J. J. Biol. Chem. 2001; 276: 24153-24159Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). cGKIβ-dependent phosphorylation of IRAG inhibits IP3-induced Ca2+ release in intact and permeabilized cells. The IRAG sequence between amino acids 152 and 184 interacts specifically with the leucine zipper of cGKIβ (33Ammendola A. Geiselhoringer A. Hofmann F. Schlossmann J. J. Biol. Chem. 2001; 276: 24153-24159Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). IRAG has a coiled-coil domain that binds in vivo with the IP3 receptor type I (32Geiselhoringer A. Werner M. Sigl K. Smital P. Worner R. Acheo L. Stieber J. Weinmeister P. Feil R. Feil S. Wegener J. Hofmann F. Schlossmann J. EMBO J. 2004; 23: 4222-4231Crossref PubMed Scopus (84) Google Scholar). Deletion of exon 12 that codes for the N-terminal part of the coiled-coil domain results in a hypomorphic IRAG allele (32Geiselhoringer A. Werner M. Sigl K. Smital P. Worner R. Acheo L. Stieber J. Weinmeister P. Feil R. Feil S. Wegener J. Hofmann F. Schlossmann J. EMBO J. 2004; 23: 4222-4231Crossref PubMed Scopus (84) Google Scholar). 8-Br-cGMP-dependent relaxation of muscarinic and α-adrenergic receptor-induced contraction of colon and aorta muscle strips, respectively, is abolished in these mice. In agreement, 8-Br-cGMP does not attenuate noradrenaline-induced Ca2+ transients in isolated aortic smooth muscle cells of IRAG mutants (32Geiselhoringer A. Werner M. Sigl K. Smital P. Worner R. Acheo L. Stieber J. Weinmeister P. Feil R. Feil S. Wegener J. Hofmann F. Schlossmann J. EMBO J. 2004; 23: 4222-4231Crossref PubMed Scopus (84) Google Scholar). However, 8-Br-cGMP-induced relaxation of K+-induced smooth muscle contraction is unchanged in the IRAG mutants. In contrast, 8-Br-cGMP is unable to affect Ca2+ release and contraction in smooth muscles from cGKI-deficient mice. These finding show for the first time that cGKI has multiple targets in vivo that contribute to smooth muscle relaxation (Fig. 1). An additional mechanism that lowers [Ca2+]i is the direct phosphorylation of Ca2+-activated maxi-K+ (BKCa) channels by cGKI. Phosphorylation increased channel opening at constant [Ca2+]i (34Alioua A. Tanaka Y. Wallner M. Hofmann F. Ruth P. Meera P. Toro L. J. Biol. Chem. 1998; 273: 32950-32956Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 35Fukao M. Mason H.S. Britton F.C. Kenyon J.L. Horowitz B. Keef K.D. J. Biol. Chem. 1999; 274: 10927-10935Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). The cGKI isozyme that phosphorylates BKCa channels is not known. Opening of BKCa channels hyperpolarizes the membrane and closes a number of channels, including L-type calcium channels, thereby reducing Ca2+ influx. This mechanism contributes to the regulation of vascular tone, as shown in wild type and cGKI-deficient mice (22Sausbier M. Schubert R. Voigt V. Hirneiss C. Pfeifer A. Korth M. Kleppisch T. Ruth P. Hofmann F. Circ. Res. 2000; 87: 825-830Crossref PubMed Scopus (206) Google Scholar). The cGKI-dependent regulation of BKCa channels depended on specific splice variants (36Zhou X.B. Schlossmann J. Hofmann F. Ruth P. Korth M. Pfluegers Arch. 1998; 436: 725-734Crossref PubMed Scopus (41) Google Scholar) and may be mediated indirectly by cGKI-dependent activation of an associated protein phosphatase 2A (37Zhou X.B. Ruth P. Schlossmann J. Hofmann F. Korth M. J. Biol. Chem. 1996; 271: 19760-19767Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 38White R.E. Lee A.B. Shcherbatko A.D. Lincoln T.M. Schonbrunn A. Armstrong D.L. Nature. 1993; 361: 263-266Crossref PubMed Scopus (226) Google Scholar). Regulation of BKCa channels cannot account for the ability of 8-Br-cGMP to relax K+-contracted smooth muscle strips of the IRAG mutant (32Geiselhoringer A. Werner M. Sigl K. Smital P. Worner R. Acheo L. Stieber J. Weinmeister P. Feil R. Feil S. Wegener J. Hofmann F. Schlossmann J. EMBO J. 2004; 23: 4222-4231Crossref PubMed Scopus (84) Google Scholar), because a change in BKCa channel activity does not affect the membrane potential under these conditions. An alternative target for cGKI is MLCP because smooth muscle tone is decreased by dephosphorylation of the RLC (39Etter E.F. Eto M. Wardle R.L. Brautigan D.L. Murphy R.A. J. Biol. Chem. 2001; 276: 34681-34685Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). MLCP is a trimer comprising a 110-130-kDa regulatory MBS also identified as myosin phosphatase targeting subunit (MYPT), a 37-kDa catalytic subunit and a 20-kDa protein of unknown function (40Hartshorne D.J. Ito M. Erdodi F. J. Biol. Chem. 2004; 279: 37211-37214Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). Several studies have shown that the inhibition of MLCP activity can be linked to increased Ca2+ sensitivity of smooth muscle contraction. Involved in this regulatory pathway are Rho kinase, arachidonic acid, and protein kinase C and its substrate CPI-17 (40Hartshorne D.J. Ito M. Erdodi F. J. Biol. Chem. 2004; 279: 37211-37214Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). Phosphorylation of MBS at Thr-696 (human sequence) by Rho kinase or MYPT1 kinase inhibits the activity of MLCP allowing phosphorylation of RLC and contraction at constant [Ca2+]i (25Somlyo A.P. Somlyo A.V. Physiol. Rev. 2003; 83: 1325-1358Crossref PubMed Scopus (1696) Google Scholar, 40Hartshorne D.J. Ito M. Erdodi F. J. Biol. Chem. 2004; 279: 37211-37214Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). MBS is phosphorylated by cGKIα at several sites (41Surks H.K. Mochizuki N. Kasai Y. Georgescu S.P. Tang K.M. Ito M. Lincoln T.M. Mendelsohn M.E. Science. 1999; 286: 1583-1587Crossref PubMed Scopus (444) Google Scholar, 42Nakamura M. Ichikawa K. Ito M. Yamamori B. Okinaka T. Isaka N. Yoshida Y. Fujita S. Nakano T. Cell Signal. 1999; 11: 671-676Crossref PubMed Scopus (52) Google Scholar). cGKIα is targeted specifically by its leucine zipper to MBS (41Surks H.K. Mochizuki N. Kasai Y. Georgescu S.P. Tang K.M. Ito M. Lincoln T.M. Mendelsohn M.E. Science. 1999; 286: 1583-1587Crossref PubMed Scopus (444) Google Scholar). cGKIα-dependent phosphorylation of MBS at Ser-695 inhibits the phosphorylation at Thr-696 and thereby the decrease in MLCP activity (43Wooldridge A.A. MacDonald J.A. Erdodi F. Ma C. Borman M.A. Hartshorne D.J. Haystead T.A. J. Biol. Chem. 2004; 279: 34496-34504Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar). This mechanism would allow a reduction in RLC phosphorylation and relaxation at constant [Ca2+]i. The individual contribution of the described cGKI-dependent mechanisms regulating smooth muscle tone might vary in different tissues. Deletion of the cGKI gene and of exon 12 of the IRAG gene suggests that phosphorylation of IRAG, BKCa channels, and MBS occurs in the same cell. However, it has been shown that modulation of the Ca2+ sensitivity is important in smooth muscles from the small intestine, whereas regulation of the [Ca2+]i appears to be more important in vascular smooth muscle. In general, these findings clearly establish that NO signals through cGKIα and cGKIβ in smooth muscle and that these isozymes use different targets to affect smooth muscle tone. Regulation of Smooth Muscle Proliferation—Migration, proliferation, and dedifferentiation of vascular smooth muscle cells are considered to be essential events in the development of atherosclerosis and vascular restenosis. Many groups have reported that NO, atrio-natriuretic peptide, and membrane-permeable cGMP analogs prevent proliferation, migration, and dedifferentiation of vascular smooth muscle cells (44Garg U.C. Hassid A. J. Clin. Invest. 1989; 83: 1774-1777Crossref PubMed Scopus (1997) Google Scholar, 45Calderone A. Thaik C.M. Takahashi N. Chang D.L. Colucci W.S. J. Clin. Invest. 1998; 101: 812-818Crossref PubMed Scopus (409) Google Scholar). Recent evidence indicates that cGKI modulates gene expression through the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway either by stimulation or by its inhibition (46Hofmann F. Ammendola A. Schlossmann J. J. Cell Sci. 2000; 113: 1671-1676Crossref PubMed Google Scholar, 47Pilz R.B. Casteel D.E. Circ. Res. 2003; 93: 1034-1046Crossref PubMed Scopus (247) Google Scholar). Differential phosphorylation of VASP might be critical in these studies. VASP, a member of the Ena/Mena/Vasp family, is an actin-binding protein that is localized to the focal adhesion and cell-to-cell contacts in many cells (48Eigenthaler M. Lohmann S.M. Walter U. Pilz R.B. Rev. Physiol. Biochem. Pharmacol. 1999; 135: 173-209Crossref PubMed Google Scholar). VASP is phosphorylated by protein kinase C, cAMP kinase, and cGKI at two sites with different preference. Recently, it was reported that expression of VASP and phosphorylation of Ser-157 increased proliferation whereas phosphorylation of Ser-239 decreased proliferation (49Chen L. Daum G. Chitaley K. Coats S.A. Bowen-Pope D.F. Eigenthaler M. Thumati N.R. Walter U. Clowes A.W. Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1403-1408Crossref PubMed Scopus (74) Google Scholar). Surprisingly, serum as used in cell culture studies stimulates phosphorylation of Ser-157 of VASP through PKC (50Chitaley K. Chen L. Galler A. Walter U. Daum G. Clowes A.W. FEBS Lett. 2004; 556: 211-215Crossref PubMed Scopus (41) Google Scholar), an effect of serum not noticed so far. In a mouse model of ischemic vessel growth, the presence of cGKI was essential for vessel growth (51Yamahara K. Itoh H. Chun T.H. Ogawa Y. Yamashita J. Sawada N. Fukunaga Y. Sone M. Yurugi-Kobayashi T. Miyashita K. Tsujimoto H. Kook H. Feil R. Garbers D.L. Hofmann F. Nakao K. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 3404-3409Crossref PubMed Scopus (141) Google Scholar). In a mouse model of atherosclerosis it was found (52Wolfsgruber W. Feil S. Brummer S. Kuppinger O. Hofmann F. Feil R. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 13519-13524Crossref PubMed Scopus (68) Google Scholar) that smooth muscle-specific deletion of cGKI retarded the development of atherosclerotic plaques and smooth muscle proliferation in vivo. In this study (52Wolfsgruber W. Feil S. Brummer S. Kuppinger O. Hofmann F. Feil R. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 13519-13524Crossref PubMed Scopus (68) Google Scholar), it was observed that stimulation of cGKI increased smooth muscle cell growth in vivo, whereas NO inhibited growth independent of cGKI. It is therefore likely that in vivo cGKI stimulates smooth muscle growth and that the existing controversy will wane as soon as better controlled experiments are initiated. Platelet Aggregation—In most cases, aggregation of platelets is initiated at areas where the endothelial cell layer has been destroyed. Endothelial cells release prostacyclin and NO, which prevent platelet adhesion and aggregation. These factors raise cAMP and cGMP levels in platelets and thereby inhibit clot formation. Platelets have a high concentration of cGKIβ that is activated in response to NO and has an anti-aggregatory function (53Massberg S. Sausbier M. Klatt P. Bauer M. Pfeifer A. Siess W. Fassler R. Ruth P. Krombach F. Hofmann F. J. Exp. Med. 1999; 189: 1255-1264Crossref PubMed Scopus (194) Google Scholar, 54Marshall S.J. Senis Y.A. Auger J.M. Feil R. Hofmann F. Salmon G. Peterson J.T. Burslem F. Watson S.P. Blood. 2004; 103: 2601-2609Crossref PubMed Scopus (76) Google Scholar, 55Gambaryan S. Geiger J. Schwarz U.R. Butt E. Begonja A. Obergfell A. Walter U. Blood. 2004; 103: 2593-2600Crossref PubMed Scopus (89) Google Scholar). Under specific conditions, cGKI may also promote platelet activation (56Li Z. Xi X. Gu M. Feil R. Ye R.D. Eigenthaler M. Hofmann F. Du X. Cell. 2003; 112: 77-86Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar), perhaps by facilitating the release of ADP (57Li Z. Zhang G. Marjanovic J.A. Ruan C. Du X. J. Biol. Chem. 2004; 279: 42469-42475Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). However, NO or cell-permeable cGMP analogs did not inhibit aggregation of cGKI-deficient platelets, whereas aggregation was prevented by cAMP-elevating agents (53Massberg S. Sausbier M. Klatt P. Bauer M. Pfeifer A. Siess W. Fassler R. Ruth P. Krombach F. Hofmann F. J. Exp. Med. 1999; 189: 1255-1264Crossref PubMed Scopus (194) Google Scholar). An intact platelet NO/cGKI signaling pathway is essential to prevent platelet aggregation after ischemia in vivo (53Massberg S. Sausbier M. Klatt P. Bauer M. Pfeifer A. Siess W. Fassler R. Ruth P. Krombach F. Hofmann F. J. Exp. Med. 1999; 189: 1255-1264Crossref PubMed Scopus (194) Google Scholar). Platelets contain two well established cGKI substrates, VASP and IRAG. Deletion of the VASP gene in mice did not grossly affect platelet aggregation (58Aszodi A. Pfeifer A. Ahmad M. Glauner M. Zhou X.H. Ny L. Andersson K.E. Kehrel B. Offermanns S. Fassler R. EMBO J. 1999; 18: 37-48Crossref PubMed Scopus (283) Google Scholar, 59Hauser W. Knobeloch K.P. Eigenthaler M. Gambaryan S. Krenn V. Geiger J. Glazova M. Rohde E. Horak I. Walter U. Zimmer M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8120-8125Crossref PubMed Scopus (193) Google Scholar), but considerably affected the interaction of platelets with the endothelium in vivo (60Massberg S. Gruner S. Konrad I. Garcia Arguinzonis M.I. Eigenthaler M. Hemler K. Kersting J. Schulz C. Muller I. Besta F. Nieswandt B. Heinzmann U. Walter U. Gawaz M. Blood. 2004; 103: 136-142Crossref PubMed Scopus (124) Google Scholar). Activation of cGKI inhibited the release of Ca2+ from IP3-sensitive stores in wild type and VASP-deficient platelets to similar extents (58Aszodi A. Pfeifer A. Ahmad M. Glauner M. Zhou X.H. Ny L. Andersson K.E. Kehrel B. Offermanns S. Fassler R. EMBO J. 1999; 18: 37-48Crossref PubMed Scopus (283) Google Scholar). Platelets express IRAG (14Geiselhoringer A. Gaisa M. Hofmann F. Schlossmann J. FEBS Lett. 2004; 575: 19-22Crossref PubMed Scopus (81) Google Scholar). Furthermore, platelets from the IRAG mutant mice (32Geiselhoringer A. Werner M. Sigl K. Smital P. Worner R. Acheo L. Stieber J. Weinmeister P. Feil R. Feil S. Wegener J. Hofmann F. Schlossmann J. EMBO J. 2004; 23: 4222-4231Crossref PubMed Scopus (84) Google Scholar, 61Geiselhöringer A. Werner M. Sigl K. Smital P. Wörner R. Acheo L. Stieber J. Weinmeister P. Feil R. Feil S. Wegener J. Hofmann F. Schlossmann J. EMBO J. 2004; 23: 4222-4231Crossref PubMed Scopus (99) Google Scholar) have a severe defect in the cGMP-mediated prevention of aggregation, 2M. Antl, F. Hofmann, and J. Schlossmann, personal communication. indicating that IRAG is an essential component of this pathway. Our knowledge about the function of cGKII is at a very preliminary state. Only three areas have been identified where cGKII plays a role: secretion, bone growth, and circadian rhythmicity. Secretion—Intestinal Cl-/fluid secretion is increased by substances that stimulate cAMP (cholera toxin) or cGMP (guanylin, STa) levels. cGKII is highly expressed in the apical membrane of the enterocytes of the small intestine. The mucosa of cGKII-deficient mice responded normally to cAMP analogues, whereas STa-induced electrogenic anion secretion was blocked. Active cGKII phosphorylated cystic fibrosis transmembrane conductance regulator and increased Cl- and water secretion. These results established that cGKII is essential for guanylin/STa-dependent secretion in the small intestine (62Pfeifer A. Aszodi A. Seidler U. Ruth P. Hofmann F. Fassler R. Science. 1996; 274: 2082-2086Crossref PubMed Scopus (342) Google Scholar, 63Vaandrager A.B. Bot A.G. Ruth P. Pfeifer A. Hofmann F. De Jonge H.R. Gastroenterology. 2000; 118: 108-114Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). NO/cGMP were reported to modulate renin release in the kidney. Deletion of the cGKI gene had no effect on renin release in isolated kidneys or kidney cells, whereas the inhibitory effect of NO on renin release was blunted in cGKII-deficient mice (64Wagner C. Pfeifer A. Ruth P. Hofmann F. Kurtz A. J. Clin. Invest. 1998; 102: 1576-1582Crossref PubMed Scopus (72) Google Scholar). Blood pressure was not affected in cGKII-/- mice. This is interesting because it was reported that activation of cGKII increased the secretion of aldosterone in rat adrenal cortical cells (65Gambaryan S. Butt E. Marcus K. Glazova M. Palmetshofer A. Guillon G. Smolenski A. J. Biol. Chem. 2003; 278: 29640-29648Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). It is possible that the opposite effect of cGKII on two blood pressure-elevating factors cancelled each other in the knock-out animals. Bone Growth—The particulate GCs, GC-A and GC-B, are expressed abundantly in mouse tibial epiphysis and vertebrae (66Suda M. Ogawa Y. Tanaka K. Tamura N. Yasoda A. Takigawa T. Uehira M. Nishimoto H. Itoh H. Saito Y. Shiota K. Nakao K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2337-2342Crossref PubMed Scopus (144) Google Scholar). Cultivation of mouse tibias in the presence of 1 μm brain-natriuretic peptide, a ligand for GC-A and GC-B, induced a significant increase in total bone length. Transgenic mice overexpressing BNP exhibited skeletal overgrowth which was restricted to those bones that grow by endochondral ossification. cGKI and -II are expressed in the growth zone of bones (62Pfeifer A. Aszodi A. Seidler U. Ruth P. Hofmann F. Fassler R. Science. 1996; 274: 2082-2086Crossref PubMed Scopus (342) Google Scholar). The deletion of cGKI has no apparent effect on the growth of the skeleton (20Pfeifer A. Klatt P. Massberg S. Ny L. Sausbier M. Hirneiss C. Wang G.X. Korth M. Aszodi A. Andersson K.E. Krombach F. Mayerhofer A. Ruth P. Fassler R. Hofmann F. EMBO J. 1998; 17: 3045-3051Crossref PubMed Scopus (455) Google Scholar). In contrast, cGKII-deficient mice are dwarfs with 16-30% shorter limbs. cGKII is essential for the CNP/cGMP-mediated endochondral ossification (67Miyazawa T. Ogawa Y. Chusho H. Yasoda A. Tamura N. Komatsu Y. Pfeifer A. Hofmann F. Nakao K. Endocrinology. 2002; 143: 3604-3610Crossref PubMed Scopus (98) Google Scholar) and regulates autonomous bone growth. Circadian Rhythmicity—The suprachiasmatic nucleus (SCN) harbors the circadian clock pacemaker that runs on a close to 24-h time scale and is reset to the external time period by multiple pathways (68Reppert S.M. Weaver D.R. Nature. 2002; 418: 935-941Crossref PubMed Scopus (3416) Google Scholar). Both cGKs are expressed in the SCN. Studies with cGKII-/- mice showed that cGKII influenced the phase shift of the circadian clock at the onset of the wheel running activity (69Oster H. Werner C. Magnone M.C. Mayser H. Feil R. Seeliger M.W. Hofmann F. Albrecht U. Curr. Biol. 2003; 13: 725-733Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). The involvement of cGKII in the regulation of the circadian clock was confirmed (70Tischkau S.A. Weber E.T. Abbott S.M. Mitchell J.W. Gillette M.U. J. Neurosci. 2003; 23: 7543-7550Crossref PubMed Google Scholar) in the isolated rat SCN, although in that system cGKII was required for night to day progression of the clock (71Tischkau S.A. Mitchell J.W. Pace L.A. Barnes J.W. Barnes J.A. Gillette M.U. Neuron. 2004; 43: 539-549Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). cGKs and the Mammalian Brain—Although cGKII is expressed in many neurons, deletion of the gene resulted only in mild neurological effects such as a moderate enhanced anxiety-like behavior and a hyposensitivity to acute alcohol intake (18Werner C. Raivich G. Cowen M. Stekalowa T. Sillaber I. Buters J.T. Spanagel R. Hofmann F. Eur. J. Neurosci. 2004; (in press)Google Scholar). Although the neuronal expression of cGKI is rather restricted, a number of important phenotypes are associated with tissue-specific deletion of cGKI (for an extensive discussion see Ref. 72Feil R. Hofmann F. Kleppisch T. Rev. Neurosci. 2004; (in press)Google Scholar). cGKIα expressed in sensory neurons of dorsal root ganglia is necessary for the correct guidance of sensory axons during embryonic development (73Schmidt H. Werner M. Heppenstall P.A. Henning M. More M.I. Kuhbandner S. Lewin G.R. Hofmann F. Feil R. Rathjen F.G. J. Cell Biol. 2002; 159: 489-498Crossref PubMed Scopus (90) Google Scholar). Recent evidence suggests that cGKIα is also involved in some forms of pain perception (74Tegeder I. Del Turco D. Schmidtko A. Sausbier M. Feil R. Hofmann F. Deller T. Ruth P. Geisslinger G. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 3253-3257Crossref PubMed Scopus (88) Google Scholar). cGKIβ is involved in hippocampal long term potentiation, a paradigm for learning, as shown in cell culture (75Arancio O. Antonova I. Gambaryan S. Lohmann S.M. Wood J.S. Lawrence D.S. Hawkins R.D. J. Neurosci. 2001; 21: 143-149Crossref PubMed Google Scholar) and in hippocampus-specific cGKI knock-out mice (76Kleppisch T. Wolfsgruber W. Feil S. Allmann R. Wotjak C.T. Goebbels S. Nave K.A. Hofmann F. Feil R. J. Neurosci. 2003; 23: 6005-6012Crossref PubMed Google Scholar). The biological significance of this finding is unclear because the cGKI mutants showed no learning defect in several tests (76Kleppisch T. Wolfsgruber W. Feil S. Allmann R. Wotjak C.T. Goebbels S. Nave K.A. Hofmann F. Feil R. J. Neurosci. 2003; 23: 6005-6012Crossref PubMed Google Scholar). The target(s) of cGKI in hippocampal and dorsal root neurons are unknown. Cerebellar Purkinje neurons express high levels of cGKIα and the G-substrate, a peptide specifically phosphorylated by cGKI. The phosphorylated G-protein is an inhibitor of protein phosphatase 1/2A (77Hall K.U. Collins S.P. Gamm D.M. Massa E. DePaoli-Roach A.A. Uhler M.D. J. Biol. Chem. 1999; 274: 3485-3495Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 78Endo S. Suzuki M. Sumi M. Nairn A.C. Morita R. Yamakawa K. Greengard P. Ito M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2467-2472Crossref PubMed Scopus (64) Google Scholar). It has been hypothesized that inhibition of the protein phosphatases allows phosphorylation of the AMPA receptor by other kinases and its internalization leading to long term depression. Indeed, coincidence of an increase in [Ca2+]i and cGKIα activity is necessary for induction of long term depression (79Lev-Ram V. Makings L.R. Keitz P.F. Kao J.P. Tsien R.Y. Neuron. 1995; 15: 407-415Abstract Full Text PDF PubMed Scopus (163) Google Scholar) and cerebellar learning (80Feil R. Hartmann J. Luo C. Wolfsgruber W. Schilling K. Feil S. Barski J.J. Meyer M. Konnerth A. De Zeeuw C.I. Hofmann F. J. Cell Biol. 2003; 163: 295-302Crossref PubMed Scopus (118) Google Scholar). Food-searching Behavior and cGKs—cGKs were also identified in a large number of invertebrates. Drosophila melanogaster has two cGK genes, dg1 and dg2 (81Kalderon D. Rubin G.M. J. Biol. Chem. 1989; 264: 10738-10748Abstract Full Text PDF PubMed Google Scholar). dg2 encodes a protein kinase that is related to the mammalian cGKI gene (1Pfeifer A. Ruth P. Dostmann W. Sausbier M. Klatt P. Hofmann F. Rev. Physiol. Biochem. Pharmacol. 1999; 135: 105-149Crossref PubMed Google Scholar, 82Fitzpatrick M.J. Sokolowski M.B. Integr. Comp. Biol. 2004; 44: 28-36Crossref PubMed Scopus (50) Google Scholar). Analysis of naturally occurring Drosophila variants in food-searching behavior indicated that a high activity of the dg2 kinase is a major determinant of rover versus sitter behavior (83Osborne K.A. Robichon A. Burgess E. Butland S. Shaw R.A. Coulthard A. Pereira H.S. Greenspan R.J. Sokolowski M.B. Science. 1997; 277: 834-836Crossref PubMed Scopus (473) Google Scholar). A similar situation has been identified in honey bees. A cGKI-like kinase activity is up-regulated when the young bees change from hive work to foraging (84Ben-Shahar Y. Robichon A. Sokolowski M.B. Robinson G.E. Science. 2002; 296: 741-744Crossref PubMed Scopus (393) Google Scholar). The opposite change has been found in Caenorhabditis elegans. In these animals, long distance roaming for food is associated with a decreased cGK activity (85Fujiwara M. Sengupta P. McIntire S.L. Neuron. 2002; 36: 1091-1102Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). Interestingly, the cGK gene involved in this behavior is more related to mammalian cGKII than to cGKI (82Fitzpatrick M.J. Sokolowski M.B. Integr. Comp. Biol. 2004; 44: 28-36Crossref PubMed Scopus (50) Google Scholar) pointing to the possibility that increased cGKII activity is related to a sedentary life style in vertebrates. The above studies unequivocally demonstrate that cGKs are involved not only in cardiovascular physiology but also regulate complex central nervous processes and that even subtle changes in cGK activities can lead to naturally occurring behavioral variants. I thank Robert Feil for reading the manuscript." @default.
W2034832260 created "2016-06-24" @default.
W2034832260 creator A5091874127 @default.
W2034832260 date "2005-01-01" @default.
W2034832260 modified "2023-10-10" @default.
W2034832260 title "The Biology of Cyclic GMP-dependent Protein Kinases" @default.
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W2034832260 doi "https://doi.org/10.1074/jbc.r400035200" @default.
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