Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

Abstract

Receptor Guanylyl Cyclase C (GC-C) was initially characterized as an important regulator of intestinal fluid and ion homeostasis. Recent findings demonstrate that GC-C is also causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. These advances have been fueled in part by identifying mutations or changes in gene expression in GC-C or its ligands, that disrupt the delicate balance of intracellular cGMP levels and are associated with a wide range of clinical phenotypes. In this review, we highlight aspects of the current knowledge of the GC-C signaling pathway in homeostasis and disease, emphasizing recent advances in the field. The review summarizes extra gastrointestinal functions for GC-C signaling, such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has expanded the homeostatic role of GC-C and implicated it in regulating the ion-microbiome-immune axis, which acts as a mechanistic driver in inflammatory bowel disease. The development of transgenic and knockout mouse models allowed for in-depth studies of GC-C and its relationship to whole-animal physiology. A deeper understanding of the various aspects of GC-C biology and their relationships with pathologies such as inflammatory bowel disease, colorectal cancer, and obesity can be leveraged to devise novel therapeutics.

Microbiota‐derived butyrate dampens linaclotide stimulation of the guanylate cyclase C pathway in patient‐derived colonoids

“…This pathway is critical for homeostatic intestinal function and defense against enteric infection, highlighting the necessity for this pathway in intestinal health. [47][48][49][50][51] In addition, the second messenger, cGMP, has been suggested to be involved in peripheral nerve modulation. 52 This feature is especially appealing as a possible therapeutic for DGBIs as the pain/visceral hypersensitivity component of this disease is exceedingly difficult to manage.…”

“…The GCC pathway was first discovered as a target for heat stable Escherichia coli enterotoxin that leads to profound secretory diarrhea and has become an attractive goal for constipation therapeutics. This pathway is critical for homeostatic intestinal function and defense against enteric infection, highlighting the necessity for this pathway in intestinal health 47–51 . In addition, the second messenger, cGMP, has been suggested to be involved in peripheral nerve modulation 52 .…”

Transcriptomic Maps of Colorectal Liver Metastasis: Machine Learning of Gene Activation Patterns and Epigenetic Trajectories in Support of Precision Medicine

“…The former plateau is associated with the epigenetic mechanisms of cellular reprogramming into plastic states, such as poised and repressed gene promoters in colonic tissue, targets of PRC2 (polycomb repressive complex 2) and of the CpG island methylation phenotype (CIMP) [45][46][47], the genes responsive for thretionin treatment via rhodopsin receptors [48], and gene signatures related to keratinization [49,50] (Supplementary Figure S5). The "processing ridge" shows distinct expression modules associating with CRC-and CRLM-related mechanisms, such as protein degradation and de-ubiquitination [51][52][53], RNA-processing, guanyl-exchange [54], and ribosomal assembly [55], as well as the adaptation of the Golgi apparatus in cancer [56].…”

CFTR High Expresser Cells in cystic fibrosis and intestinal diseases

“…At the same time, Na + absorption is inhibited through NHE3, impeding fluid absorption from the lumen. As a consequence, duodenal pH increases to prevent epithelial damage and increase fluid secretion [ 93 ]. Neutralization of the duodenal pH is also important for preventing dysbiosis [ 94 ] and promoting fat metabolism, since pancreatic lipase is inactivated at low pH.…”