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Science 20 December 1996:
Vol. 274. no. 5295, pp. 2082 - 2086
DOI: 10.1126/science.274.5295.2082
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Reports

Intestinal Secretory Defects and Dwarfism in Mice Lacking cGMP-Dependent Protein Kinase II

Alexander Pfeifer, * Attila Aszódi, dagger Ursula Seidler, dagger Peter Ruth, Franz Hofmann, Reinhard Fässler

Cyclic guanosine 3',5'-monophosphate (cGMP)-dependent protein kinases (cGKs) mediate cellular signaling induced by nitric oxide and cGMP. Mice deficient in the type II cGK were resistant to Escherichia coli STa, an enterotoxin that stimulates cGMP accumulation and intestinal fluid secretion. The cGKII-deficient mice also developed dwarfism that was caused by a severe defect in endochondral ossification at the growth plates. These results indicate that cGKII plays a central role in diverse physiological processes.

A. Pfeifer, P. Ruth, F. Hofmann, Institut für Pharmakologie und Toxikologie, Technische Universität München, Biedersteiner Strasse 29, D-80802 München, Germany.
A. Aszódi and R. Fässler, Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany.
U. Seidler, Medizinische Klinik I, Eberhard-Karls-Universität Tübingen, D-72076 Tübingen, Germany.
*   To whom correspondence should be addressed. E-mail: pfeifer{at}ipt.med.tu-muenchen.de

dagger    These authors contributed equally to the work.

Nitric oxide (NO) and a broad spectrum of hormones, drugs, and toxins raise intracellular cGMP concentrations and thereby regulate a great variety of functions, including smooth muscle relaxation, neuronal excitability, and epithelial electrolyte transport (1). Depending on the tissue, the increase in cGMP concentrations leads to the activation of different receptors, such as cyclic nucleotide phospodiesterases, cGMP-regulated ion channels, and cGK (2). Although the major effects of cGMP have been attributed to the activation of cGK, its physiological role is still controversial (2, 3). It has been suggested that cGMP effects are mediated in some cell types by cross-activation of adenosine 3',5'-monophosphate (cAMP) kinase (cAK) (3), which shares high homology in the cyclic nucleotide binding domains with the cGKs (4). The identification of the physiological mediator of cGMP is further complicated by the existence of two forms of cGK, type I and type II, which are encoded by distinct genes (5). Smooth muscle, platelets, and cerebellum contain high concentrations of the type I cGK, whereas cGKII is highly concentrated in brain, lung, and intestinal mucosa (5, 6). The function of cGKII is not well understood, although there is evidence that it mediates intestinal secretion of water and electrolyte induced by the E. coli toxin STa and the intestinal peptide guanylin (7).

To investigate the physiological roles of cGKII, we generated mice carrying a null mutation of the cGKII gene (cGKII-/- mice) (8). The enzyme structure and the targeting vector are shown in Fig. 1A. The deletion of the cGKII gene was confirmed by Northern (RNA) blotting (Fig. 1C), reverse transcriptase-polymerase chain reaction (RT-PCR) (Fig. 1D), and immunoblotting of intestinal, brain, and lung extracts (Fig. 1E). Assays of jejunal homogenates for cGMP-stimulated phosphotransferase activity (9) confirmed that there was no residual cGKII activity in the mutant mice (Fig. 1G). A deficiency of cGKII had no effect on the integrity of the intestinal cGMP pathway proximal to the kinase, as assayed by STa-stimulated guanylyl cyclase activity (Fig. 1G). Immunoblot analysis indicated that expression of cGKI or the catalytic subunits of cAK was not affected by the absence of cGKII (Fig. 1, E and F). Heterozygous matings of outbred and inbred mice produced viable pups (n = 202) with the expected Mendelian frequency. These mice were also fertile as adults, suggesting that embryonic and fetal development of cGKII-deficient animals was not impaired.


Fig. 1. Targeted disruption of the cGKII gene. (A) Structure of cGKII showing the cGMP-binding pockets (boxed A and B), ATP-binding, and catalytic domain are shown in the top diagram. Localization, restriction map, and organization of exons (filled boxes) and introns (lines) of the cGKII target locus are shown in the second diagram. The targeting vector pNTKK2LS, third diagram, contains 6.2 kb of cGKII genomic sequence that flanks the neomycin resistance cassette (neor). The insertion deletes a 308-bp Bam HI-Hinc II fragment of the second coding exon and of the following intron. The disrupted exon (nucleotides 903 to 1070) (5) encodes the first part of the cGMP binding pocket. The bottom diagram shows the structure of the homologous recombination product. Abbreviations: B, Bam HI; R, Eco RV; K, Kpn I; H, Hinc II; S, Sma I; tk, herpes simplex virus thymidine kinase gene; and P, probe. (B) Identification of cGKII+/+, cGKII+/-, and cGKII-/- mice by Southern (DNA) blot analysis. Hybridization of Eco RV-digested genomic DNA with probe P results in a 3.5-kb mutant-specific band. (C) Northern blot of total RNA extracted from the jejunum of cGKII+/+, cGKII+/-, and cGKII-/- mice. The blot was hybridized with mouse cGKII cDNA sequences (nucleotides 690 to 1308) (5). (D) RT-PCR (8) of RNA isolated from the small intestine of cGKII+/+ and cGKII-/- mice with primers that amplify cGKII (top) and guanylin (Gua) (bottom). (E) Immunoblot analysis (8) of cGKII (top) and cGKI (bottom) expression in the duodenum, brain, and lung. (F) Immunoblot analysis of cAK expression in duodenum (8). (G) (Left) cGMP-stimulated protein kinase activity (9) in the homogenates from mucosal scrapings (BB) of the small intestine. (Right) Guanylyl cyclase activity stimulated by STa was determined in brush border membranes isolated from cGKII+/+ and cGKII-/- mice. (H) Immunoblots of the BB membranes, used for analysis of kinase activity, and the complete duodenum (Duo), containing the mucosa and the muscularis, which were probed with antibodies to cGKII and cGKI (8). [View Larger Versions of these Images (141K GIF file)]

We first tested the effects of cGKII deficiency on intestinal fluid secretion. The cAMP- and cGMP-signaling cascades are key regulators of intestinal chloride and water secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) (3, 7). Some studies have suggested that cGKII mediates the pathophysiological effects of E. coli STa (6, 7), a heat-stable enterotoxin that increases cellular cGMP concentrations and induces diarrhea (10), whereas other studies have implicated cross-activation of cAK in these effects (3). We studied electrogenic anion secretion in small intestine and caecum (11) by measuring the short-circuit current (Isc) of mucosal segments (12) treated with STa, cGMP, and cAMP (Fig. 2A). The Isc of the mouse small intestine is mainly due to CFTR-regulated Cl- conductance (13). As expected, treatment of mucosal segments from normal mice with 100 nM STa led to a significant stimulation of Isc that was further increased by the addition of 0.2 mM and 1 mM 8-bromo-cGMP (8-BrcGMP) (Fig. 2A). Maximum stimulation of Isc was obtained by superfusion with 1 mM 8-bromo-cAMP (8-BrcAMP). In contrast to these findings, cGKII-null mice showed only a marginal stimulation of Isc after STa treatment that was not increased by the addition of 0.2 mM or 1 mM 8-BrcGMP. Jejunal mucosa of cGKII-deficient mice responded normally to 1 mM 8-BrcAMP, demonstrating that the absence of cGKII selectively disrupts the STa-cGMP but not the cAMP pathway.


Fig. 2. Effect of E. coli STa on epithelial electrolyte transport and fluid accumulation in the intestine. (A) Epithelial electrolyte transport in stripped mucosa sections from the jejunum of wild-type (blacksquare ) and cGKII-null (bullet ) mice. The transepithelial electric potential difference was measured in Ussing chamber setups, and the short-circuit current (Isc) was calculated as in (12). The mucosa sections were treated sequentially with 1 µM tetrodotoxin (a), 100 nM STa (b), 0.2 mM 8-BrcGMP (c), 1 mM 8-BrcGMP (d), and 1 mM 8-BrcAMP (e). Thereafter the tissues were exposed to 100 µM bumetanide (f), which blocks basolateral cotransport of Na+, K+, and 2Cl-, and to 500 µM ouabain (g), which blocks Na+ and K+ adenosine triphosphatase. The values are mean ± SEM of five mice for each treatment. (B) STa and CT-induced diarrhea in intact mice. Fluid secretion into the intestine was measured as the gut weight: carcass weight ratios in cGKII+/+, cGKII+/-, and cGKII-/- mice after treatment with STa or CT. Controls (PBS) were injected with PBS. (The asterisk indicates P < 0.05, Student's t test.) [View Larger Versions of these Images (50K GIF file)]

To evaluate the pathophysiological significance of these observations, we induced secretory diarrhea in newborn mice by intragastric injection of STa (14). Fluid secretion into the intestine of the live animal can be quantified by determining the ratio of gut weight to carcass weight (g/c ratio): g/c ratios greater than 0.083 indicate a diarrheal response, whereas ratios less than 0.074 indicate no response to STa (10). In the cGKII+/+ and cGKII+/- mice, STa induced the accumulation of clear fluid in the intestine, and the g/c ratio increased to 0.092 ± 0.006 (n = 5) and to 0.088 ± 0.004 (n = 5), respectively (Fig. 2B). In contrast, cGKII-/- mice showed no accumulation of fluid in the intestine after STa treatment. This lack of response to STa was reflected by a g/c ratio of 0.062 ± 0.002 (n = 5) (Fig. 2B). However, inactivation of cGKII did not affect the secretory response to agents that raise intestinal cAMP concentrations such as cholera toxin (CT) (Fig. 2B).

As the cGKII-/- mice grew, dwarfism, short limbs (micromelia), and cranial abnormalities became apparent. The difference in body length between cGKII+/+ and cGKII-/- mice (15) increased until it reached a constant level at 8 to 10 weeks (Fig. 3A). At this age the mutant mice were 16% shorter and weighed 14% less than their cGKII+/+ littermates. X-ray analysis (Fig. 3B) and staining of skeletons with alizarin-red (16) revealed a 23 to 30% reduction in the length of the long bones and vertebrae (Fig. 3C). In contrast, the size and weight of the organs within the shortened trunk of cGKII-null mice were normal (16), resulting in a distended abdomen (Fig. 3B). The serum electrolyte levels, bone density, and total body fat (16) of the cGKII-null mice were also normal. These findings, together with the detection of cGKII mRNA in the chondrocytes of the developing bone by in situ hybridization (Fig. 3G), suggest that cGKII has a direct role in bone growth.

Fig. 3. Analysis of the phenotype in bone and of cGK expression in the growth plate (15). (A) Time course of body length, measured from the nose to the anus, of cGKII+/+ (bullet ) and cGKII-/- (blacksquare ) male mice. Female mice showed similar differences (16). The length of cGKII-/- mice differed significantly from control mice beginning from the third week (P < 0.05, n = 7 to 17 per point). (B) X-ray of 8-week-old cGKII-null mouse (top) and normal littermate (bottom). Bar, 1 cm. (C) Length of tibia (Ti), femur (Fe), ulna (Ul), humerus (Hu), vertebra (Ve), and clavicle (Cl) of 8- to 10-week-old cGKII+/+ (open bars) and cGKII-/- (shaded bars) male mice (asterisk indicates P < 0.05 versus control, n = 4). (D) Hematoxylin-eosin staining of tibia of a newborn mouse (bar, 200 µm). (E and F) Immunohistochemical analysis of cGK expression in tibial growth plates of a newborn mouse with antibodies to GKII (E) and cGKI (F) (bar, 200 µm). (G and H) In situ hybridization of tibial sections from a 16.5-day-old embryo with a cGKII-specific antisense (G) and sense (H) probe. Darkfield illumination; bar, 200 µm. P, proliferative zone; H, hypertrophic zone. [View Larger Version of this Image (61K GIF file)]

The normal development of membranous bones like the clavicles (Fig. 3C) and bones of the cranial vault but not of the base of the cranium suggested that the cGKII-null mutation specifically inhibited endochondral but not membranous ossification. During endochondral ossification, bone is deposited on a calcified cartilage matrix that is produced by the growth plate (17). The growth plate is responsible for linear skeletal growth and is characterized by the transition from resting to proliferative to hypertrophic chondrocytes, typically in orderly columnar arrays (17) (Figs. 3D and 4A).

Fig. 4. Analysis of the skeletal defect of cGKII-deficient mice. (A and B) Sections of the growth plates of tibiae stained with hematoxylin-eosin from 4-week-old wild-type (A) and cGKII-null (B) mice. Zones of proliferative (P) and hypertrophic (H) chondrocytes, as well as the height of the growth plates (arrowheads), are indicated. Bars, 200 µm. (C and D) [3H]Thymidine labeling of proliferative cells (white arrows) in the growth plates of 3-week-old cGKII+/+ (C) and cGKII-/- (D) mice. The arrowheads indicate the height of the growth plate. Darkfield illumination; bars, 200 µm. (E) Transplantation of femurs between cGKII+/+ and cGKII-/- inbred mice. The increase in length within 14 days after subcutaneous implantation was measured as percent increase from the start value. Red indicates the data for cGKII-/- donors or recipients. An asterisk indicates P < 0.05 versus control (n = 6). [View Larger Version of this Image (47K GIF file)]

To determine whether growth plate chondrocytes express cGK, we did immunohistochemical stainings with antibodies specific for the two cGK enzymes. Immunohistochemistry for cGKII provided specific staining of a population of chondrocytes located at the border between the proliferative and hypertrophic zone (Fig. 3E). In addition, a weak staining was observed in early proliferative and resting chondrocytes (Fig. 3E). The staining was not present in the cGKII-/- animals and also could be competed with purified recombinant cGKII (16). We could also detect cGKI expression in the growth plate that was confined to the hypertrophic zone (Fig. 3F). Preincubation of the cGKI-specific antibody with purified cGKI protein (20 µg/ml) abolished the signal. The cGKI expression pattern and density were not affected by the absence of cGKII (16). In situ hybridization studies (Fig. 3, G and H) confirmed the predominant expression of cGKII in the late proliferative and early hypertrophic chondrocytes.

Histological examination of long bones did not reveal substantial abnormalities in newborn cGKII-/- mice. Starting at the first week postpartum, the cGKII-/- mice developed severe defects in the axial organization of the growth plate, which were most prominent at 3 to 4 weeks of age (Fig. 4B). At this age, cGKII-null mice showed significant changes in growth plate histology consisting of irregular and broadened hypertrophic zones with patches of nonhypertrophic cells intermingled with hypertrophic chondrocytes, even close to the area of vascular invasion. These cells were identified as proliferative chondrocytes by [3H]thymidine incorporation (Fig. 4, C and D). In contrast to the wild-type mice (Fig. 4A), the cGKII-null mice showed no clear separation between the proliferative and hypertrophic zone (Fig. 4B). At 6 to 8 weeks of age, cGKII+/+ and cGKII-/- growth plates became smaller, but the mutants showed wedge-shaped columns of mixed hypertrophic and proliferative chondrocytes protruding into the trabecular bone (16).

To exclude the possibility that malabsorption or imbalances in hormones or growth factors were responsible for the retarded growth of the skeleton, we transplanted (15) mutant and normal long bones into normal mice. Whereas the length of normal long bones increased 23 ± 4% (n = 6), the mutant bones grew only marginally when transplanted into normal mice (Fig. 4E). Furthermore, long bones explanted from wild-type mice developed normally when implanted into cGKII-deficient mice (Fig. 4E). These results suggest that the growth defect in the mutant mice is not due to a general metabolic disturbance.

The phenotype of the cGKII-deficient mice point to a central role for cGKII in diverse physiological processes. The identification of the pathway that mediates intestinal fluid secretion by E. coli STa has potential medical implications, because STa causes traveller's diarrhea and about 50% of infant mortality in developing countries (10). Finally the unexpected link between cGKII and bone growth may be an important step for understanding the pathophysiology for a range of bone and joint diseases.

REFERENCES AND NOTES

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  8. cGKII DNA was isolated from a genomic library made from 129/Sv mouse tissue (Genome Systems). A 1.4-kb Hinc II-Bam HI and a 4.8-kb Hinc II-Sma I fragment of the cGKII gene was cloned 5' and 3' of the neomycin resistance expression cassette (neor). The herpes simplex virus thymidine kinase cassette (tk) was cloned 3' to the cGKII sequence. R1 embryonic stem (ES) cells [A. Nagy, J. Rossant, R. Nagy, W. Abramow-Newerly, J. C. Roder, Proc. Natl. Acad. Sci. U.S.A. 90, 8424 (1993) [Medline]] were electroporated with the linearized vector and plated on irradiated G418-resistant embryonic feeder cells [ R. Fässler and M. Meyer, Genes Dev. 9, 1896 (1995) [Medline]]. Recombinant clones were selected with G418 (0.3 mg/ml) and 1-[2'-deoxy-2'-fluoro-beta -D-arabinofuranosyl-]-5-iodouracil (FIAU) (0.2 µM). Four of 100 double-resistant colonies showed homologous recombination at the cGKII locus. Germline chimeras were obtained by injection of mutant ES cell clones into C57Bl/6 blastocysts. RT-PCR was performed with primers that amplify cGKII (nucleotides 508 to 1740) (5) and guanylin (nucleotides 331 to 521) [D. Sciaky, J. L. Kosiba, M. B. Cohen, Genomics 24, 583 (1994) [Medline]], respectively. Immunoblot analysis was performed with antibody (Ab) B32-A3 to the COOH-terminal region of mouse cGKII, Ab A16-14 to cGKI, and Ab to the alpha , beta , and gamma  catalytic subunits of the cAK (Santa Cruz Biotechnology, Santa Cruz, CA).
  9. The intestine was removed from freshly killed mice and purged with phosphate-buffered saline (PBS). The epithelial cells were scraped from the mucosal surface and resuspended in 20 mM KH2PO4, pH 7.0, 2 mM EDTA, and 2 mM benzamidine (for kinase determination) or in 10 mM tris-HCl (pH 7.4), 300 mM sorbitol, 2 mM benzamidine, and leupeptin (20 µg/ml) (for guanylate cyclase activity). The kinase activity was determined as described [P. Ruth et al., Eur. J. Biochem. 202, 1339 (1991) [Medline]], with 10 µg of protein and in the presence or absence of 30 µM cGMP. GC activity in brush border membranes was determined as described [A. B. Vaandrager, S. Schulz, H. R. De Jonge, D. L. Garbers, J. Biol. Chem. 268, 2174 (1993) [Medline]], with 35 µg of protein and 400 ng of STa. The samples were acetylated and cGMP concentrations were determined in an enzyme immunoassay (Cayman, Ann Arbor, MI). Values are expressed as the mean ± SEM with n = 8 for kinase activity and n = 4 for guanyly cyclase activity.
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  11. The midpart of the jejunum was excised and opened longitudinally. All muscle layers were removed with a forceps under the stereomicroscope. The mucosa was mounted between two lucite half-chambers (0.125 cm2 of exposed area) in an Ussing chamber (World Precision Instruments, Berlin) apparatus. The serosal and luminal solutions were circulated by a gas-lift system and were identical except that indomethacin (10 µM) and glucose (2 mM) were present in the serosal perfusate, and mannitol (2 mM) in the luminal perfusate. The perfusate solutions contained 140.5 mM Na+, 4.5 mM K+, 2 mM Ca2+, 1.3 mM Mg2+, 126 mM Cl-, 1.3 mM SO42-, 20 mM HCO3-, and 1.5 mM HPO42-, were gassed with 5% CO2-95% O2, and were kept at 37°C.
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  14. The suckling mouse model (10) was used to quantify the STa-induced diarrhea in vivo. STa (50 ng) was dissolved in 0.5 ml of isotonic PBS and injected intragastrically in 3- to 4-day-old mice. After a 2-hour incubation at 25°C, the whole intestine without stomach was carefully removed and weighed. The g/c ratio was calculated as the ratio of gut weight to remaining carcass weight. To evaluate the response to CT, we used the sealed mouse model [S. H. Richardson, J. C. Giles, K. S. Kruger, Infect. Immun. 43, 482 (1984) [Medline]]. Data are expressed as mean ± SEM of five mice for each treatment. P < 0.05 versus control.
  15. Bone length was determined by x-ray analysis and by analysis of alizarin-red-stained skeletons. Data are expressed as mean ± SEM. For immunohistochemistry, knees were fixed in 95% ethanol overnight and cut in 6-µm sections. Sections were incubated for 1 hour with Abs to cGKI and cGKII (8). The primary Abs were visualized by using a biotinylated secondary Ab (antibody to rabbit immunoglobulin G), followed by avidin-peroxidase complex and developed with H2O2-3,3'-diaminobenzidintetrahydrochlorid (Vectastain, Burlinghome, CA). For in situ hybridization, specimens were fixed in 4% paraformaldehyde overnight, embedded in paraffin, and cut in 6-µm sections. In situ hybridization was performed with a cGKII cDNA probe (nucleotides 960 to 1719) (5). [3H]Thymidine labeling of growth plates was performed as described [A. M. Reimold et al., Nature 379, 262 (1996) [Medline]], and bone transplantation was performed as described by W. J. L. Felts [Transplant. Bull. 4, 5 (1957)]. Femurs of 1-week-old donors were implanted subcutaneously into 4- to 6-week-old recipients. After 14 days, the mice were killed and the length of the femurs was determined.
  16. A. Pfeifer et al., data not shown.
  17. A. Erlebacher, E. H. Filvaroff, S. E. Gitelman, R. Derynck, Cell 80, 371 (1995) [Medline]; E. B. Hunziker, R. K. Schenk, L. M. Cruz-Orive, J. Bone Jt. Surg. 69, 162 (1987).
  18. We thank K. Kühn for his advice; M. Walter, M. Guba, and I. Blumenstein for their help in the Ussing chamber experiments; K. Doerr, S. Kamm, and S. Benkert for technical assistance; and P. Klatt for help in quantifying the total body fat of the mice. Supported by grants from the Deutsche Forschungs Gemeinschaft, Bundesministerium für Forschung und Technologie, and Fonds der Chemie. R.F. was supported by the Hermann and Lilly Schilling Stiftung.

9 July 1996; accepted 2 October 1996


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Endocr. Rev. 27, 47-72
   Abstract »    Full Text »    PDF »
Cyclic Guanosine 5'-Monophosphate-Dependent Protein Kinase II Is Induced by Luteinizing Hormone and Progesterone Receptor-Dependent Mechanisms in Granulosa Cells and Cumulus Oocyte Complexes of Ovulating Follicles.
V. Sriraman, M. D. Rudd, S. M. Lohmann, S. M. Mulders, and J. S. Richards (2006)
Mol. Endocrinol. 20, 348-361
   Abstract »    Full Text »    PDF »
Function of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion.
F. Hofmann, R. Feil, T. Kleppisch, and J. Schlossmann (2006)
Physiol Rev 86, 1-23
   Abstract »    Full Text »    PDF »
Cyclic GMP-dependent Protein Kinase Regulates CCAAT Enhancer-binding Protein {beta} Functions through Inhibition of Glycogen Synthase Kinase-3.
X. Zhao, S. Zhuang, Y. Chen, G. R. Boss, and R. B. Pilz (2005)
J. Biol. Chem. 280, 32683-32692
   Abstract »    Full Text »    PDF »
STa and cGMP stimulate CFTR translocation to the surface of villus enterocytes in rat jejunum and is regulated by protein kinase G.
F. Golin-Bisello, N. Bradbury, and N. Ameen (2005)
Am J Physiol Cell Physiol 289, C708-C716
   Abstract »    Full Text »    PDF »
Expression and Function of cGMP-dependent Protein Kinase Type I during Medaka Fish Embryogenesis.
T. Yamamoto and N. Suzuki (2005)
J. Biol. Chem. 280, 16979-16986
   Abstract »    Full Text »    PDF »
A Loss-of-Function Mutation in Natriuretic Peptide Receptor 2 (Npr2) Gene Is Responsible for Disproportionate Dwarfism in cn/cn Mouse.
T. Tsuji and T. Kunieda (2005)
J. Biol. Chem. 280, 14288-14292
   Abstract »    Full Text »    PDF »
The Biology of Cyclic GMP-dependent Protein Kinases.
F. Hofmann (2005)
J. Biol. Chem. 280, 1-4
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Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs.
N. Tamura, L. K. Doolittle, R. E. Hammer, J. M. Shelton, J. A. Richardson, and D. L. Garbers (2004)
PNAS 101, 17300-17305
   Abstract »    Full Text »    PDF »
Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
H. Chikuda, F. Kugimiya, K. Hoshi, T. Ikeda, T. Ogasawara, T. Shimoaka, H. Kawano, S. Kamekura, A. Tsuchida, N. Yokoi, et al. (2004)
Genes & Dev. 18, 2418-2429
   Abstract »    Full Text »    PDF »
Analysis of Drosophila cGMP-dependent Protein Kinases and Assessment of Their in Vivo Roles by Targeted Expression in a Renal Transporting Epithelium.
M. R. MacPherson, S. M. Lohmann, and S.-A. Davies (2004)
J. Biol. Chem. 279, 40026-40034
   Abstract »    Full Text »    PDF »
cGMP and a germ-line signal control body size in C. elegans through cGMP-dependent protein kinase EGL-4.
Y. Nakano, Y. Nagamatsu, and Y. Ohshima (2004)
Genes Cells 9, 773-779
   Abstract »    Full Text »    PDF »
The dg2 (for) gene confers a renal phenotype in Drosophila by modulation of cGMP-specific phosphodiesterase.
M. R. MacPherson, K. E. Broderick, S. Graham, J. P. Day, M. D. Houslay, J. A. T. Dow, and S. A. Davies (2004)
J. Exp. Biol. 207, 2769-2776
   Abstract »    Full Text »    PDF »
In Search of Food: Exploring the Evolutionary Link Between cGMP-Dependent Protein Kinase (PKG) and Behaviour.
M. J. Fitzpatrick and M. B. Sokolowski (2004)
Integr. Comp. Biol. 44, 28-36
   Abstract »    Full Text »    PDF »
Mechanisms for the control of body size by a G-kinase and a downstream TGF{beta} signal pathway in Caenorhabditis elegans.
Y. Nagamatsu and Y. Ohshima (2004)
Genes Cells 9, 39-47
   Abstract »    Full Text »    PDF »
A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion.
S. P. Rao, Z. Sellers, D. L. Crombie, D. L. Hogan, E. A. Mann, D. Childs, S. Keely, M. Sheil-Puopolo, R. A. Giannella, K. E. Barrett, et al. (2004)
Am J Physiol Gastrointest Liver Physiol 286, G95-G101
   Abstract »    Full Text »    PDF »
Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System: Insights From Genetically Modified Mice.
R. Feil, S. M. Lohmann, H. de Jonge, U. Walter, and F. Hofmann (2003)
Circ. Res. 93, 907-916
   Abstract »    Full Text »    PDF »
Physiology and Pathophysiology of Vascular Signaling Controlled by Cyclic Guanosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase.
T. Munzel, R. Feil, A. Mulsch, S. M. Lohmann, F. Hofmann, and U. Walter (2003)
Circulation 108, 2172-2183
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cGMP-dependent Protein Kinase Type II Regulates Basal Level of Aldosterone Production by Zona Glomerulosa Cells without Increasing Expression of the Steroidogenic Acute Regulatory Protein Gene.
S. Gambaryan, E. Butt, K. Marcus, M. Glazova, A. Palmetshofer, G. Guillon, and A. Smolenski (2003)
J. Biol. Chem. 278, 29640-29648
   Abstract »    Full Text »    PDF »
Autophosphorylation of cGMP-dependent Protein Kinase Type II.
A. B. Vaandrager, B. M. Hogema, M. Edixhoven, C. M. M. van den Burg, A. G. M. Bot, P. Klatt, P. Ruth, F. Hofmann, J. Van Damme, J. Vandekerckhove, et al. (2003)
J. Biol. Chem. 278, 28651-28658
   Abstract »    Full Text »    PDF »
Synergism between Calcium and Cyclic GMP in Cyclic AMP Response Element-Dependent Transcriptional Regulation Requires Cooperation between CREB and C/EBP-{beta}.
Y. Chen, S. Zhuang, S. Cassenaer, D. E. Casteel, T. Gudi, G. R. Boss, and R. B. Pilz (2003)
Mol. Cell. Biol. 23, 4066-4082
   Abstract »    Full Text »    PDF »
CNP gene expression is activated by Wnt signaling and correlates with Wnt4 expression during renal injury.
K. Surendran and T. C. Simon (2003)
Am J Physiol Renal Physiol 284, F653-F662
   Abstract »    Full Text »    PDF »
Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C. elegans.
T. Hirose, Y. Nakano, Y. Nagamatsu, T. Misumi, H. Ohta, and Y. Ohshima (2003)
Development 130, 1089-1099
   Abstract »    Full Text »    PDF »
Vasopressin-dependent Inhibition of the C-type Natriuretic Peptide Receptor, NPR-B/GC-B, Requires Elevated Intracellular Calcium Concentrations.
S. E. Abbey and L. R. Potter (2002)
J. Biol. Chem. 277, 42423-42430
   Abstract »    Full Text »    PDF »
Cyclic GMP-Dependent Protein Kinase II Plays a Critical Role in C-Type Natriuretic Peptide-Mediated Endochondral Ossification.
T. Miyazawa, Y. Ogawa, H. Chusho, A. Yasoda, N. Tamura, Y. Komatsu, A. Pfeifer, F. Hofmann, and K. Nakao (2002)
Endocrinology 143, 3604-3610
   Abstract »    Full Text »    PDF »
cGMP-dependent Protein Kinase Ibeta Physically and Functionally Interacts with the Transcriptional Regulator TFII-I.
D. E. Casteel, S. Zhuang, T. Gudi, J. Tang, M. Vuica, S. Desiderio, and R. B. Pilz (2002)
J. Biol. Chem. 277, 32003-32014
   Abstract »    Full Text »    PDF »
Guanylin and Functional Coupling Proteins in the Human Salivary Glands and Gland Tumors : Expression, Cellular Localization, and Target Membrane Domains.
H. Kulaksiz, E. Rehberg, W. Stremmel, and Y. Cetin (2002)
Am. J. Pathol. 161, 655-664
   Abstract »    Full Text »    PDF »
Toxoplasma gondii Cyclic GMP-Dependent Kinase: Chemotherapeutic Targeting of an Essential Parasite Protein Kinase.
R. G. K. Donald, J. Allocco, S. B. Singh, B. Nare, S. P. Salowe, J. Wiltsie, and P. A. Liberator (2002)
Eukaryot. Cell 1, 317-328
   Abstract »    Full Text »    PDF »
Clara cell impact in air-side activation of CFTR in small pulmonary airways.
H. Kulaksiz, A. Schmid, M. Honscheid, A. Ramaswamy, and Y. Cetin (2002)
PNAS 99, 6796-6801
   Abstract »    Full Text »    PDF »
Guanylin, Uroguanylin, and Heat-stable Euterotoxin Activate Guanylate Cyclase C and/or a Pertussis Toxin-sensitive G Protein in Human Proximal Tubule Cells.
A. Sindice, C. Basoglu, A. Cerci, J. R. Hirsch, R. Potthast, M. Kuhn, Y. Ghanekar, S. S. Visweswariah, and E. Schlatter (2002)
J. Biol. Chem. 277, 17758-17764
   Abstract »    Full Text »    PDF »
Transgenesis by lentiviral vectors: Lack of gene silencing in mammalian embryonic stem cells and preimplantation embryos.
A. Pfeifer, M. Ikawa, Y. Dayn, and I. M. Verma (2002)
PNAS 99, 2140-2145
   Abstract »    Full Text »    PDF »
Dwarfism and early death in mice lacking C-type natriuretic peptide.
H. Chusho, N. Tamura, Y. Ogawa, A. Yasoda, M. Suda, T. Miyazawa, K. Nakamura, K. Nakao, T. Kurihara, Y. Komatsu, et al. (2001)
PNAS
   Abstract »    Full Text »
Renal effects of serine-7 analog of lymphoguanylin in ex vivo rat kidney.
M. C. Fonteles, S. L. Carrithers, H. S. A. Monteiro, A. F. Carvalho, G. R. Coelho, R. N. Greenberg, and L. R. Forte (2001)
Am J Physiol Renal Physiol 280, F207-F213
   Abstract »    Full Text »    PDF »
Endothelial Nitric Oxide Synthase Gene-Deficient Mice Demonstrate Marked Retardation in Postnatal Bone Formation, Reduced Bone Volume, and Defects in Osteoblast Maturation and Activity.
J. Aguirre, L. Buttery, M. O'Shaughnessy, F. Afzal, I. Fernandez de Marticorena, M. Hukkanen, P. Huang, I. MacIntyre, and J. Polak (2001)
Am. J. Pathol. 158, 247-257
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Highly specific, membrane-permeant peptide blockers of cGMP-dependent protein kinase Ialpha inhibit NO-induced cerebral dilation.
W. R. G. Dostmann, M. S. Taylor, C. K. Nickl, J. E. Brayden, R. Frank, and W. J. Tegge (2000)
PNAS 97, 14772-14777
   Abstract »    Full Text »    PDF »
Genetic Models Reveal That Brain Natriuretic Peptide Can Signal through Different Tissue-Specific Receptor-Mediated Pathways.
H. Chusho, Y. Ogawa, N. Tamura, M. Suda, A. Yasoda, T. Miyazawa, I. Kishimoto, Y. Komatsu, H. Itoh, K. Tanaka, et al. (2000)
Endocrinology 141, 3807-3813
   Abstract »    Full Text »    PDF »
Expression of GC-C, a Receptor-Guanylate Cyclase, and Its Endogenous Ligands Uroguanylin and Guanylin along the Rostrocaudal Axis of the Intestine.
X. Qian, S. Prabhakar, A. Nandi, S. S. Visweswariah, and M. F. Goy (2000)
Endocrinology 141, 3210-3224
   Abstract »    Full Text »    PDF »
Guanylyl Cyclases and Signaling by Cyclic GMP.
K. A. Lucas, G. M. Pitari, S. Kazerounian, I. Ruiz-Stewart, J. Park, S. Schulz, K. P. Chepenik, and S. A. Waldman (2000)
Pharmacol. Rev. 52, 375-414
   Abstract »    Full Text »    PDF »
Localization of cGMP-Dependent Protein Kinase Isoforms in Mouse Eye.
D. M. Gamm, L. K. Barthel, P. A. Raymond, and M. D. Uhler (2000)
Invest. Ophthalmol. Vis. Sci. 41, 2766-2773
   Abstract »    Full Text »
Binding and Phosphorylation of a Novel Male Germ Cell-specific cGMP-dependent Protein Kinase-anchoring Protein by cGMP-dependent Protein Kinase Ialpha.
K. Yuasa, K. Omori, and N. Yanaka (2000)
J. Biol. Chem. 275, 4897-4905
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Endothelial Nitric-oxide Synthase (Type III) Is Activated and Becomes Calcium Independent upon Phosphorylation by Cyclic Nucleotide-dependent Protein Kinases.
E. Butt, M. Bernhardt, A. Smolenski, P. Kotsonis, L. G. Frohlich, A. Sickmann, H. E. Meyer, S. M. Lohmann, and H. H. H. W. Schmidt (2000)
J. Biol. Chem. 275, 5179-5187
   Abstract »    Full Text »    PDF »
Guanylin peptides: renal actions mediated by cyclic GMP.
L. R. Forte, R. M. London, R. H. Freeman, and W. J. Krause (2000)
Am J Physiol Renal Physiol 278, F180-F191
   Abstract »    Full Text »    PDF »
Rising behind NO: cGMP-dependent protein kinases.
F Hofmann, A Ammendola, and J Schlossmann (2000)
J. Cell Sci. 113, 1671-1676
   Abstract »    PDF »
A Novel Interaction of cGMP-dependent Protein Kinase I with Troponin T.
K. Yuasa, H. Michibata, K. Omori, and N. Yanaka (1999)
J. Biol. Chem. 274, 37429-37434
   Abstract »    Full Text »    PDF »
Serine 19 of Human 6-Pyruvoyltetrahydropterin Synthase Is Phosphorylated by cGMP Protein Kinase II.
T. Scherer-Oppliger, W. Leimbacher, N. Blau, and B. Thony (1999)
J. Biol. Chem. 274, 31341-31348
   Abstract »    Full Text »    PDF »
Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3).
J. Jaubert, F. Jaubert, N. Martin, L. L. Washburn, B. K. Lee, E. M. Eicher, and J.-L. Guenet (1999)
PNAS 96, 10278-10283
   Abstract »    Full Text »    PDF »
Structure and activity of OK-GC: a kidney receptor guanylate cyclase activated by guanylin peptides.
R. M. London, S. L. Eber, S. S. Visweswariah, W. J. Krause, and L. R. Forte (1999)
Am J Physiol Renal Physiol 276, F882-F891
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Atrial natriuretic peptide-stimulated Ca2+ reabsorption in rabbit kidney requires membrane-targeted, cGMP-dependent protein kinase type II.
J. G. J. Hoenderop, A. B. Vaandrager, L. Dijkink, A. Smolenski, S. Gambaryan, S. M. Lohmann, H. R. de Jonge, P. H. G. M. Willems, and R. J. M. Bindels (1999)
PNAS 96, 6084-6089
   Abstract »    Full Text »    PDF »
Increased Adhesion and Aggregation of Platelets Lacking Cyclic Guanosine 3',5'-Monophosphate Kinase I.
S. Massberg, M. Sausbier, P. Klatt, M. Bauer, A. Pfeifer, W. Siess, R. Fassler, P. Ruth, F. Krombach, and F. Hofmann (1999)
J. Exp. Med. 189, 1255-1264
   Abstract »    Full Text »    PDF »
Long-Term Potentiation in the Hippocampal CA1 Region of Mice Lacking cGMP-Dependent Kinases Is Normal and Susceptible to Inhibition of Nitric Oxide Synthase.
T. Kleppisch, A. Pfeifer, P. Klatt, P. Ruth, A. Montkowski, R. Fassler, and F. Hofmann (1999)
J. Neurosci. 19, 48-55
   Abstract »    Full Text »    PDF »
Control of CFTR Channel Gating by Phosphorylation and Nucleotide Hydrolysis.
D. C. GADSBY and A. C. NAIRN (1999)
Physiol Rev 79, 77-107
   Abstract »    Full Text »    PDF »
Tissue Distribution, Cellular Source, and Structural Analysis of Rat Immunoreactive Uroguanylin.
M. Nakazato, H. Yamaguchi, Y. Date, M. Miyazato, K. Kangawa, M. F. Goy, N. Chino, and S. Matsukura (1998)
Endocrinology 139, 5247-5254
   Abstract »    Full Text »    PDF »
1,25-Dihydroxyvitamin D3 upregulates natriuretic peptide receptor-C expression in mouse osteoblasts.
N. Yanaka, H. Akatsuka, E. Kawai, and K. Omori (1998)
Am J Physiol Endocrinol Metab 275, E965-E973
   Abstract »    Full Text »    PDF »
Protein kinase G expression in the small intestine and functional importance for smooth muscle relaxation.
A. Huber, P. Trudrung, M. Storr, H. Franck, V. Schusdziarra, P. Ruth, and H.-D. Allescher (1998)
Am J Physiol Gastrointest Liver Physiol 275, G629-G637
   Abstract »    Full Text »    PDF »
Endogenous or overexpressed cGMP-dependent protein kinases inhibit cAMP-dependent renin release from rat isolated perfused kidney, microdissected glomeruli, and isolated juxtaglomerular cells.
S. Gambaryan, C. Wagner, A. Smolenski, U. Walter, W. Poller, W. Haase, A. Kurtz, and S. M. Lohmann (1998)
PNAS 95, 9003-9008
   Abstract »    Full Text »    PDF »
Natriuretic Peptide Regulation of Endochondral Ossification. EVIDENCE FOR POSSIBLE ROLES OF THE C-TYPE NATRIURETIC PEPTIDE/GUANYLYL CYCLASE-B PATHWAY.
A. Yasoda, Y. Ogawa, M. Suda, N. Tamura, K. Mori, Y. Sakuma, H. Chusho, K. Shiota, K. Tanaka, and K. Nakao (1998)
J. Biol. Chem. 273, 11695-11700
   Abstract »    Full Text »    PDF »
Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide.
M. Suda, Y. Ogawa, K. Tanaka, N. Tamura, A. Yasoda, T. Takigawa, M. Uehira, H. Nishimoto, H. Itoh, Y. Saito, et al. (1998)
PNAS 95, 2337-2342
   Abstract »    Full Text »    PDF »
Membrane targeting of cGMP-dependent protein kinase is required for cystic fibrosis transmembrane conductance regulator Cl- channel activation.
Arie. B. Vaandrager, A. Smolenski, B. C. Tilly, A. B. Houtsmuller, E. M. E. Ehlert, A. G. M. Bot, M. Edixhoven, W. E. M. Boomaars, S. M. Lohmann, and H. R. de Jonge (1998)
PNAS 95, 1466-1471
   Abstract »    Full Text »    PDF »
Signaling Pathways for Guanylin and Uroguanylin in the Digestive, Renal, Central Nervous, Reproductive, and Lymphoid Systems.
X. Fan, Y. Wang, R. M. London, S. L. Eber, W. J. Krause, R. H. Freeman, and L. R. Forte (1997)
Endocrinology 138, 4636-4648
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Hepatocyte nuclear factor-1alpha regulates transcription of the guanylin gene.
J. A. Hochman, D. Sciaky, T. L. Whitaker, J. A. Hawkins, and M. B. Cohen (1997)
Am J Physiol Gastrointest Liver Physiol 273, G833-G841
   Abstract »    Full Text »    PDF »
Natural Behavior Polymorphism Due to a cGMP-Dependent Protein Kinase of Drosophila.
K. A. Osborne, A. Robichon, E. Burgess, S. Butland, R. A. Shaw, A. Coulthard, H. S. Pereira, R. J. Greenspan, and M. B. Sokolowski (1997)
Science 277, 834-836
   Abstract »    Full Text »
Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta.
M. Moser, A. Pscherer, C. Roth, J. Becker, G. Mucher, K. Zerres, C. Dixkens, J. Weis, L. Guay-Woodford, R. Buettner, et al. (1997)
Genes & Dev. 11, 1938-1948
   Abstract »    Full Text »    PDF »
Endogenous Type II cGMP-dependent Protein Kinase Exists as a Dimer in Membranes and Can Be Functionally Distinguished from the Type I Isoforms.
A. B. Vaandrager, M. Edixhoven, A. G. M. Bot, M. A. Kroos, T. Jarchau, S. Lohmann, H.-G. Genieser, and H. R. de Jonge (1997)
J. Biol. Chem. 272, 11816-11823
   Abstract »    Full Text »    PDF »
The Amino-terminal Cyclic Nucleotide Binding Site of the Type II cGMP-dependent Protein Kinase Is Essential for Full Cyclic Nucleotide-dependent Activation.
M. K. Taylor and M. D. Uhler (2000)
J. Biol. Chem. 275, 28053-28062
   Abstract »    Full Text »    PDF »
Activation of Protein Kinase C Stimulates the Dephosphorylation of Natriuretic Peptide Receptor-B at a Single Serine Residue. A POSSIBLE MECHANISM OF HETEROLOGOUS DESENSITIZATION.
L. R. Potter and T. Hunter (2000)
J. Biol. Chem. 275, 31099-31106
   Abstract »    Full Text »    PDF »
Molecular Determinants of the Interaction between the Inositol 1,4,5-Trisphosphate Receptor-associated cGMP Kinase Substrate (IRAG) and cGMP Kinase Ibeta.
A. Ammendola, A. Geiselhoringer, F. Hofmann, and J. Schlossmann (2001)
J. Biol. Chem. 276, 24153-24159
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Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice.
P. Hedlund, A. Aszodi, A. Pfeifer, P. Alm, F. Hofmann, M. Ahmad, R. Fassler, and K.-E. Andersson (2000)
PNAS 97, 2349-2354
   Abstract »    Full Text »    PDF »
Dwarfism and early death in mice lacking C-type natriuretic peptide.
H. Chusho, N. Tamura, Y. Ogawa, A. Yasoda, M. Suda, T. Miyazawa, K. Nakamura, K. Nakao, T. Kurihara, Y. Komatsu, et al. (2001)
PNAS 98, 4016-4021
   Abstract »    Full Text »    PDF »
cGMP-Dependent Protein Kinase I Mediates the Negative Inotropic Effect of cGMP in the Murine Myocardium.
J. W. Wegener, H. Nawrath, W. Wolfsgruber, S. Kuhbandner, C. Werner, F. Hofmann, and R. Feil (2002)
Circ. Res. 90, 18-20
   Abstract »    Full Text »    PDF »


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