Neuronal cGMP kinase I is essential for stimulation of duodenal bicarbonate secretion by luminal acid

Singh, Anurag Kumar; Spießberger, Beate; Zheng, Wei; Xiao, Fang; Łukowski, Robert; Wegener, Jörg W.; Weinmeister, Pascal; Saur, Dieter; Klein, Sabine; Schemann, Michael; Krueger, Dagmar; Seidler, Ursula; Hofmann, Franz

doi:10.1096/fj.11-200394

Cited by 21 publications

(24 citation statements)

References 39 publications

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“…This is a very important finding because with age cGKI-SM mice suffer from gastrointestinal bleedings, which might be related to severe hematological changes, including a high platelet count. 42 Despite these well-known effects of interleukin-6 on megakaryopoiesis, the role of interleukin-6 on in vivo functions of megakaryocytes, such as motility, positioning, and dynamic processes of platelet release, has not been investigated in detail. Using multiphoton intravital microscopy to visualize megakaryocytes within BM in vivo, we found that interleukin-6 increases the megakaryocyte volume in vivo ( Figure 6A).…”

Section: Discussionmentioning

confidence: 99%

Thrombocytosis as a Response to High Interleukin-6 Levels in cGMP-Dependent Protein Kinase I Mutant Mice

Zhang

Łukowski

Gaertner

et al. 2013

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; cGKI L2/L2 mice and cGKI-deficient bone marrow-chimeras. Accordingly, antibody-mediated blockade of interleukin-6 normalized platelet counts in cGKI-SM mice. Conclusions-Abnormal cGMP/cGKI signaling in nonhematopoietic cells affects thrombopoiesis via elevated interleukin-6production and results in thrombocytosis in vivo. Dysfunction of cGMP/cGKI signaling in nonhematopoietic cells contributes to a high platelet count, which is potentially associated with thrombosis. Zhang et al Thrombocytosis in cGKI-Deficient Mice 1821membrane system, and the synthesis of platelet-specific proteins and granules. 11 Together, these changes give rise to the platelet production machinery of mature megakaryocytes that release thrombocytes into the bone marrow (BM)-sinusoid vessels via long cytoplasmic processes, termed proplatelets. 12Fundamental functions of cAMP/cGMP signaling in mature platelets have been recognized for many years [13][14][15] ; however, the role of cAMP or cGMP in the maturation of megakaryocytes and the production of platelets in vivo are much less known. Recent in vitro findings indicate that platelet release from fetal liver cells-derived megakaryocytes is enhanced by high cGMP, but blocked by high cAMP levels in response to prostaglandin I 2 or agonists that directly activate adenylyl cyclase. 16 As in many other cell types, the rate of cGMP production through soluble guanylyl cyclase activity and its degradation via cGMP-hydrolyzing phospodiesterases (PDEs) determine the amplitude, duration, and spatiotemporal distribution of an intraplatelet cGMP signal. 17 Of the 3 known platelet PDE isoforms, 2 isoforms, PDE-2 and PDE-3, may maintain an intensive cross-talk between nitric oxide (NO)/soluble guanylyl cyclase/cGMP and prostaglandin I 2 /adenylyl cyclase/ cAMP because these PDEs limit, with different affinities for their substrates and with different catalytic rates, the levels of both cyclic nucleotides, producing either inactive 5´-AMP or 5´-GMP. 18 Most effects of high intraplatelet cGMP are directly mediated by cGMP-dependent protein kinase type I (cGKI), which is presumably the major effector of NO/cGMP in many cells. 13,14 Interestingly, mature platelets express only the cGKIβ isozyme, whereas in numerous other cell types, such as hippocampal neurons and vascular or visceral smooth muscle (SM) cells, 2 cGKI isoforms, cGKIα and cGKIβ, act downstream of NO and cGMP. 19 In platelets, NO/cGMP signaling via cGKIβ efficiently opposes most agonist-induced and Ca 2+-dependent activation/aggregation steps. 13,20,21 However, the effect of cGKI on megakaryopoiesis and platelet biogenesis in vivo is not completely known.To study the role of cGMP/cGKI signaling in megakaryopoiesis and platelet production in vivo, we took advantage of several established or recently generated transgenic mouse lines. 22Interestingly, we detected high platelet counts in conventional cGKI-null mutants (cGKI L1/L1 ) and in adult cGKI-SM mice with cGKI expression specifically restored in SM, but not in other cell types, 22 whe...

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Section: Discussionmentioning

confidence: 99%

Thrombocytosis as a Response to High Interleukin-6 Levels in cGMP-Dependent Protein Kinase I Mutant Mice

Zhang

Łukowski

Gaertner

et al. 2013

ATVB

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“…2 The inhibition of gastric proton secretion by PPI results in a neutral gastric fluid, allowing for the healing of the ulcer and thereby stopping the blood loss. This was sufficient to reverse the severe anemia in cGKI -/-and cGKI RM mice.…”

Section: Letters To the Editormentioning

confidence: 99%

“…Therefore, we conclude that chronic intestinal bleeding, and not the decreased lifespan of erythrocytes due to eryptosis, is the major cause of anemia in these animals. Remarkably, the reversal of anemia prolongs the survival of the cGKI -/-mice, 2 suggesting that the premature death of cGKI -/-mice is at least partially caused by severe anemia.…”

Section: Letters To the Editormentioning

confidence: 99%

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Iron deficiency anemia in cyclic GMP kinase knockout mice

et al. 2016

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“…However, we want to point out that the presented study shows preliminary data with regard to the mouse models used, because either conventional cGKI À/À or aRM mice were studied. These mice have multiple defects that are not related to the fat cell mass [21,22,30,31,[39][40][41][42]. Therefore, we cannot delineate whether or not the deletion of cGKI in fat cells was the essential cause of the reported disturbance in some fat cell parameters in vivo.…”

Section: Discussionmentioning

confidence: 99%