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

Abstract

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

Impaired Intestinal Sodium Transport in Inflammatory Bowel Disease: From the Passenger to the Driver's Seat

“…PKGII and PKA phosphorylate and activate the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel leading to increased chloride and water secretion. PKGII mediated phosphorylation and inhibition of NHE3 results in reduced intestinal sodium absorption ( Figure 1C) [26,30]. Indeed, cGMP-mediated NHE3 inhibition may underlie attenuation of NHE3 transport activity reported in some patients with UC, despite its preserved expression and cellular localization [31].…”

“…GC-C is a multi-domain protein consisting of an extracellular ligand-binding domain (ECD), a transmembrane domain, a juxta-membrane domain, a kinase homology domain (KHD), a linker region, a guanylyl cyclase domain (GCD), and a C-terminal domain [26]. GC-C is also expressed in extraintestinal tissues, such as the brain and adipose tissue, but its role in these tissues is not clearly understood [26,30]. Ligands of GC-C include endogenous hormones, guanylin and uroguanylin, and heat-stable enterotoxin (ST) produced by enterotoxigenic Escherichia coli (ETEC).…”

“…Homozygous and compound heterozygous mutations that inactivate or truncate GC-C cause meconium ileus, as a result of reduced intestinal fluid and ion secretion. In contrast, increased cGMP production due to activating mutations in GC-C results in congenital sodium diarrhoea and IBD ( Figure 2A and Table 1) [18,28,30]. The underlying mechanism in these cases may be the reduction of Na + absorption due to GC-C/cGMP-mediated inhibition of NHE3 activity, along with an increase in chloride secretion via Figure 2A) [30].…”

“…In contrast, increased cGMP production due to activating mutations in GC-C results in congenital sodium diarrhoea and IBD ( Figure 2A and Table 1) [18,28,30]. The underlying mechanism in these cases may be the reduction of Na + absorption due to GC-C/cGMP-mediated inhibition of NHE3 activity, along with an increase in chloride secretion via Figure 2A) [30]. A summary of clinical features present in patients with IBD, and location and properties of the mutations, are presented below.…”

“…The guanylyl cyclase domain (GCD) is the catalytic domain of GC-C. It consists of a conserved class III cyclase domain fold where cGMP synthesis occurs ( Figure 2C) [26,30]. In 2012, we reported the first case of a pathological mutation in GC-C in 32 individuals (14 females and 18 males) of a Norwegian family with relatively mild, chronic secretory diarrhoea and dysmotility (Familial Diarrhoea Syndrome) (Diarrhoea 6; OMIM 614616).…”