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Appetite Control in C. elegans
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
Kristen Davis, Mi Cheong Cheong, Ji Su Park, Young-Jai You
The cGMP signaling pathway is involved in many essential functions; it regulates phototransduction in the eyes, hypertension, reproduction, attention and hyperactive behavior, vasodilation, circadian rhythms, intestinal homeostasis, and cancer progression (Januszewicz 1995, Oster et al. 2003, Yau and Hardie 2009, Francis et al. 2010, Zhang et al. 2010, Gong et al. 2011, Arshad and Visweswariah 2012, Kim et al. 2013). In addition, it regulates body size, exploratory behavior, stress-induced development, sleep, and feeding in invertebrates (Fujiwara et al. 2002, Raizen et al. 2008, You et al. 2008). Its role in appetite control and obesity was first discovered in C. elegans and later in mammals (Valentino et al. 2011). In mammals, a gut peptide, uroguanylin, is released upon feeding and binds to GUCY2C, its receptor in the hypothalamus, to suppress feeding (Valentino et al. 2011). GUCY2C is a membrane guanylyl cyclase (GCY) that produces cGMP upon its activation. Interestingly, there are several previous studies that suggest cGMP functions in obesity. For instance, sildenafil, a medicine that inhibits degradation of cGMP to treat erectile dysfunction, has protective effects in weight gain on a high-fat diet (Ayala et al. 2007, Mitschke et al. 2013). NPs that bind to NP receptors (also GCYs) to produce cGMP are not only important to control blood pressure and heart function (Takei 2001) but also play an important role in lipolysis in adipose tissue via phosphorylation of hormone sensitive lipase by cGMP-dependent protein kinase (PKG) (Sengenes et al. 2000). Furthermore, epidemiological studies show that a certain allele of the NP receptor type C gene is associated with a lean phenotype (Sarzani et al. 2004), suggesting a critical role of NP in fat metabolism.
Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2021
Ariana A. Entezari, Adam E. Snook, Scott A. Waldman
The loss of guanylin hormone early in colorectal cancer, together with the intestinal epithelial dysfunction that occurs in the GUCY2C-deficient mouse model, suggests that colorectal cancer may arise within an environment of ligand deficiency that silences GUCY2C signaling [18,61]. This suggests that reconstituting GUCY2C signaling with exogenous ligands might be used as a strategy to regulate intestinal cell proliferation to prevent tumorigenesis. In that context, diet-induced obesity suppresses guanylin expression supporting tumorigenesis in mice, and that transformation can be blocked by overexpression of guanylin [63]. Additionally, in an Apcmin/+ mouse model, oral uroguanylin administration inhibits tumorigenesis, suggesting that activation of GUCY2C signaling might be a strategy for cancer chemoprevention [64].
An update on guanylyl cyclase C in the diagnosis, chemoprevention, and treatment of colorectal cancer
Published in Expert Review of Clinical Pharmacology, 2020
Jeffrey A. Rappaport, Scott A. Waldman
Guanylyl cyclases are an enzyme class responsible for the catalysis of guanosine triphosphate (GTP) to the second messenger, cGMP [4,47]. GUCY2C is a transmembrane receptor expressed on the brush border of the intestinal epithelium. Its endogenous ligands, collectively known as guanylins, are small peptide hormones secreted by the epithelium into the intestinal lumen. Uroguanylin, secreted in the small intestine, and guanylin, secreted in the large intestine, are synthesized as propeptides and processed into 16-mer and 15-mer mature peptides, respectively [48,49]. Both mature peptides harbor two disulfide bonds, conferring stability in the intestinal lumen. This paracrine hormone axis, regulated by the guanylins and GUCY2C, canonically controls intestinal secretion. Agonist stimulation of the GUCY2C extracellular ligand binding domain activates its intracellular catalytic domain, leading to the production of cGMP. cGMP in turn targets several effector proteins, including cGMP-dependent protein kinases (PKGs), phosphodiesterases (PDEs), and cGMP-gated ion channels [4]. Direct activation of PKG II, as well as indirect activation of protein kinase A, drives phosphorylation and translocation of the cystic fibrosis transmembrane regulator (CFTR) to the cell surface [50–52]. Simultaneously, PKG inhibits the apical Na+/H+ exchanger (NHE3) also present on the cell surface [50–52]. Together, modulation of these channels results in HCO3− and Cl− secretion, with Na+ retention in the intestinal lumen; this osmotic gradient results in fluid secretion into the intestine.
Plecanatide for the treatment of chronic idiopathic constipation in adult patients
Published in Expert Review of Clinical Pharmacology, 2019
Gabrio Bassotti, Paolo Usai Satta, Massimo Bellini
Uroguanylin is primarily expressed in the slightly acidic (pH 5–6) regions of the duodenum and jejunum [32]. Binding of uroguanylin to the GC-C receptor leads to accumulation of intracellular cGMP [33], which helps to maintain fluid and electrolyte balance, promotes visceral analgesia, and reduces inflammation in the gastrointestinal tract. Overstimulation of the GC-C receptor provokes an uncontrolled release of electrolytes and water into the intestinal lumen, resulting in diarrhea [30]. Subsequently, pharmacologic agonists to the GC-C receptor were developed to treat patients with CIC and IBS-C. In particular, linaclotide showed to be an acid synthetic peptide homolog of E. coli heat-stable enterotoxin, and plecanatide a natural analog to native uroguanylin [34]. Although both drugs are GC-C receptor agonists, there are pharmacologic differences, with plecanatide retaining the pH dependent receptor binding characteristics of uroguanylin.