Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor

Carrithers, Stephen L.; Ott, Cobern E.; Hill, Michael J.; Johnson, Brett; Cai, Weiyan; Chang, Jason J.; Shah, Rajesh G.; Sun, Congmei; Mann, Elizabeth A.; Fonteles, M. C.; Forte, Leonard R.; Giannella, Ralph A.; Greenberg, Richard N.

doi:10.1111/j.1523-1755.2004.00375.x

Cited by 87 publications

(101 citation statements)

References 70 publications

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“…However, in the absence of either cognate receptors mediating extralumenal responses to these peptides (18,19) or defined homeostatic mechanisms regulating their endocrine secretion from the gut (20), the precise physiological significance of the GUCY2C endocrine axis remains ambiguous. In the context of the central role of the gut-neural axis in controlling nutrient consumption and the importance of guanylyl cyclase activity in central control of invertebrate feeding, we explored the role of GUCY2C signaling in appetite regulation.…”

Section: Introductionmentioning

confidence: 99%

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino

Lin²,

Snook³

et al. 2011

J. Clin. Invest.

139

275

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Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.

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Section: Introductionmentioning

confidence: 99%

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino

Lin²,

Snook³

et al. 2011

J. Clin. Invest.

139

275

View full text Add to dashboard Cite

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“…These mice are resistant to intestinal secretion produced by STa (33)(34)(35), but approximately 10% of the intestinal binding sites for these peptides are still present when compared with wildtype mice. In the kidney, guanylin peptides still induce saluresis and diuresis in these GC-C-deficient mice (36), strongly suggesting an additional receptor and possibly signaling cascade for guanylin peptides at least in the kidney and to some extent also in the intestine. That renal effects of guanylin peptides are maintained when GC-C is absent also indicates that GC-C plays no or only a minor role for these peptides in the kidney.…”

Section: Gc-cmentioning

confidence: 91%

“…Indeed, in the human proximal tubule cell line, UGN inhibited Na ϩ /H ϩ exchange activity (Schlatter E., unpublished results). As mentioned above, guanylin peptides still cause natriuresis, kaliuresis, and diuresis in GC-C-deficient mice, suggesting a second receptor in the kidney for these peptides (36). In addition to this GC-C-and cGMP-dependent signaling pathway, UGN can activate a pertussis toxin-sensitive G-protein that leads to activation of a K ϩ conductance (61).…”

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 97%

“…Guanylin peptides increase the secretion of Na ϩ , K ϩ , and water in the kidney without changes in GFR or renal blood flow (7,36). UGN is proposed to be an intestinal natriuretic peptide, as natriuresis produced by oral salt load is decreased in UGNdeficient mice (51).…”

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 99%

“…It is evident from this scheme that the guanylin peptides are the first peptides identified that act in this nephron segment primarily on K ϩ channels without directly affecting Na ϩ channels. In the human CCD, the depolarization of principal cells via inhibition of the secretory K ϩ channels results in natriuresis as the predominant effect observed in vivo with these peptides (7,36,67). Reduced Na ϩ reabsorption also decreases water reabsorption in this nephron segment and thus causes diuresis.…”

Section: Signaling Mechanisms Of Guanylin Peptides In the Kidneymentioning

confidence: 99%

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Cellular Effects of Guanylin and Uroguanylin

Sinđić

Schlatter

2006

Journal of the American Society of Nephrology

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Ingestion of a salty meal induces secretion of guanylin (GN) and uroguanylin (UGN) into the intestinal lumen, where they inhibit Na ؉ absorption and induce Cl ؊ , HCO 3 ؊ , and water secretion. Simultaneously, these hormones stimulate renal electrolyte excretion by inducing natriuresis, kaliuresis, and diuresis. GN and UGN therefore participate in the prevention of hypernatremia and hypervolemia after salty meals. The signaling pathway of GN and UGN in the intestine is well known. They activate enterocytes via guanylate cyclase C (GC-C), which leads to cGMP-dependent inhibition of Na ؉ /H ؉ exchange and activation of the cystic fibrosis transmembrane regulator. In GC-C-deficient mice, GN and UGN still produce renal natriuresis, kaliuresis, and diuresis, suggesting different signaling pathways in the kidney compared with the intestine. Signaling pathways for GN and UGN in the kidney differ along the various nephron segments. In proximal tubule cells, a cGMP-and GC-C-dependent signaling was demonstrated for both peptides. In addition, UGN activates a pertussis toxinsensitive G-protein-coupled receptor. A similar dual signaling pathway is also known for atrial natriuretic peptide. Recently, a cGMP-independent signaling pathway for GN and UGN was also shown in principal cells of the human and mouse cortical collecting duct. Because GN and UGN activate different signaling pathways in specific organs and even within the kidney, this review focuses on more recent findings on cellular effects and signaling mechanisms of these peptides and their pathophysiologic implications in the intestine and the kidney.

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Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease‐related mutations

2020

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Guanylyl cyclase C (GC-C) is the receptor for the heat-stable enterotoxin, which causes diarrhea, and the endogenous ligands, guanylin and uroguanylin. GC-C is predominantly expressed in the intestinal epithelium and regulates fluid and ion secretion in the gut. The receptor has a complex domain organization, and in the absence of structural information, mutational analysis provides clues to mechanisms of regulation of this protein. Here, we review the mutational landscape of this receptor that reveals regulatory features critical for its activity. We also summarize the available information on mutations in GC-C that have been reported in humans and contribute to severe gastrointestinal abnormalities. Since GC-C is also expressed in extraintestinal tissues, it is likely that mutations thus far reported in humans may also affect other organ systems, warranting a close observation of these patients in future. K E Y W O R D ScGMP, guanylyl cyclase C, human mutation, meconium ileus, secretory diarrhea

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Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor

Cited by 87 publications

References 70 publications

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Cellular Effects of Guanylin and Uroguanylin

Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease‐related mutations

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