Transmembrane guanylate cyclase in intestinal pathophysiology

Steinbrecher, Kris A.; Cohen, Mitchell B.

doi:10.1097/mog.0b013e328341ead5

Cited by 22 publications

(15 citation statements)

References 71 publications

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“…Finally and strikingly, the existing seven MGCs—ANF-RGC, CNP-RGC, STa-RGC, ROS-GC1, ROS-GC2, ONE-GC, GC-GC—in a specific fashion, by synthesizing cellular second messenger cyclic GMP, are linked with the physiological processes of blood pressure regulation, cellular growth, sensory transductions, neural plasticity, memory, temperature sensing (reviewed in Sharma et al, 2016) and, with tumor suppression (reviewed in Steinbrecher and Cohen, 2011; Windham and Tinsley, 2015). This study demonstrates that all these functions converge to a common site, CCD, which through a unified signal transduction mode, control these activities.…”

Section: Resultsmentioning

confidence: 99%

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

Ravichandran

Duda

Pertzev

et al. 2017

Front. Mol. Neurosci.

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Membrane guanylate cyclase (MGC) is a ubiquitous multi-switching cyclic GMP generating signaling machine linked with countless physiological processes. In mammals it is encoded by seven distinct homologous genes. It is a single transmembrane spanning multi-modular protein; composed of integrated blocks and existing in homo-dimeric form. Its core catalytic domain (CCD) module is a common transduction center where all incoming signals are translated into the production of cyclic GMP, a cellular signal second messenger. Crystal structure of the MGC’s CCD does not exist and its precise identity is ill-defined. Here, we define it at a sub-molecular level for the phototransduction-linked MGC, the rod outer segment guanylate cyclase type 1, ROS-GC1. (1) The CCD is a conserved 145-residue structural unit, represented by the segment V820-P964. (2) It exists as a homo-dimer and contains seven conserved catalytic elements (CEs) wedged into seven conserved motifs. (3) It also contains a conserved 21-residue neurocalcin δ-modulated structural domain, V836-L857. (4) Site-directed mutagenesis documents that each of the seven CEs governs the cyclase’s catalytic activity. (5) In contrast to the soluble and the bacterium MGC which use Mn2+-GTP substrate for catalysis, MGC CCD uses the natural Mg2+-GTP substrate. (6) Strikingly, the MGC CCD requires anchoring by the Transmembrane Domain (TMD) to exhibit its major (∼92%) catalytic activity; in isolated form the activity is only marginal. This feature is not linked with any unique sequence of the TMD; there is minimal conservation in TMD. Finally, (7) the seven CEs control each of four phototransduction pathways- -two Ca2+-sensor GCAPs-, one Ca2+-sensor, S100B-, and one bicarbonate-modulated. The findings disclose that the CCD of ROS-GC1 has built-in regulatory elements that control its signal translational activity. Due to conservation of these regulatory elements, it is proposed that these elements also control the physiological activity of other members of MGC family.

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Section: Resultsmentioning

confidence: 99%

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

Ravichandran

Duda

Pertzev

et al. 2017

Front. Mol. Neurosci.

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“…Consistent with the importance of PKG2 downstream of cGMP, both guanylin (44) and GCC (36) knockout animals also showed less pronounced homeostatic effects in the distal colon. Some controversy exists concerning GCC-dependent homeostasis in the small intestine (42). The reduced effect of PKG2 deficiency in the distal colon likely Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These ligands bind to guanylyl cyclase C receptors (GCC) expressed on the surface of intestinal epithelial cells (IEC) and trigger intracellular cGMP production (42). Effectors for cGMP include phosphodiesterases, ion channels, and cGMPdependent protein kinases (PKG) (27).…”

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confidence: 99%

Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa

Wang

Kwon

Thangaraju

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Signaling through cGMP has emerged as an important regulator of tissue homeostasis in the gastrointestinal tract, but the mechanism is not known. Type 2 cGMP-dependent protein kinase (PKG2) is a major cGMP effector in the gut epithelium, and the present studies have tested its importance in the regulation of proliferation and differentiation in the mouse colon and in colon cancer cell lines. Tissue homeostasis was examined in the proximal colon of Prkg2(-/-) mice using histological markers of proliferation and differentiation. The effect of ectopic PKG2 on proliferation and differentiation was tested in vitro using inducible colon cancer cell lines. PCR and luciferase reporter assays were used to determine the importance of Sox9 downstream of PKG2. The colons of Prkg2(-/-) mice exhibited crypt hyperplasia, increased epithelial apoptosis, and reduced numbers of differentiated goblet and enteroendocrine cells. Ectopic PKG2 was able to inhibit proliferation and induce Muc2 and CDX2 expression in colon cancer cells, but did not significantly affect cell death. PKG2 reduced Sox9 levels and signaling, suggesting possible involvement of this pathway downstream of cGMP in the colon. The work presented here demonstrates a novel antiproliferative and prodifferentiation role for PKG2 in the colon. These homeostatic functions of PKG2 were reproducible in colon cancer cells lines where downregulation of Sox9 is a possible mechanism. The similarities in phenotype between PKG2 and GCC knockout mice positions PKG2 as a likely mediator of the homeostatic effects of cGMP signaling in the colon.

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“…8 Uroguanylin and guanylin are endogenous peptide hormones that trigger intracellular cGMP production by activating guanylyl cyclase C receptors (GC-C) in the intestinal epithelium. 13,14 This system is well established in the regulation of fluid and electrolyte balance, 15 but has emerged more recently as fundamentally important for the maintenance of epithelial homeostasis and barrier integrity. Mice that are deficient in either guanylin or GC-C have reduced cGMP levels, an increased proliferative compartment, increased apoptosis, and reduced differentiation of secretory lineage cells in the intestine.…”

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confidence: 99%

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

Wang

Islam

Bridges

et al. 2017

The American Journal of Pathology

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Signaling through cGMP has therapeutic potential in the colon, where it has been implicated in the suppression of colitis and colon cancer. In this study, we tested the ability of cGMP and type 2 cGMPdependent protein kinase (PKG2) to activate forkhead box O (FoxO) in colon cancer cells and in the colon epithelium of mice. We show that activation of PKG2 in colon cancer cells inhibited cell proliferation, inhibited AKT, and activated FoxO. Treatment of colon explants with 8Br-cGMP also activated FoxO target gene expression at both RNA and protein levels, and reduced epithelial reduction-oxidation (redox) stress. FoxO3a was the most prominent isoform in the distal colon epithelium, with prominent luminal staining. FoxO3a levels were reduced in Prkg2 À/À animals, and FoxO target genes were unaffected by 8Br-cGMP challenge in vitro. Treatment of mice with the phosphodiesterase-5 inhibitor vardenafil (Levitra) mobilized FoxO3a to the nucleus of luminal epithelial cells, which corresponded to increased FoxO target gene expression, reduced redox stress, and increased epithelial barrier integrity. Treatment of human colonic biopsy specimens with 8Br-cGMP also activated catalase and manganese superoxide dismutase expression, indicating that this pathway is conserved in humans. Taken together, these results identify a novel signaling pathway in the colon epithelium, where FoxO tumor suppressors could provide protection from redox stress. Moreover, this pathway is regulated by endogenous cGMP/PKG2 signaling, and can be targeted using phosphodiesterase-5 inhibitors. (Am J Pathol 2017, 187: 377e389; http://dx

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Transmembrane guanylate cyclase in intestinal pathophysiology

Cited by 22 publications

References 71 publications

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

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