What is the role of Guanylate Cyclase-C (GC-C)?

From the Guidelines

Guanylate Cyclase-C (GC-C) agonists, such as linaclotide, are the most effective treatment option for chronic idiopathic constipation, with a recommended dose of 72μg or 145μg daily. The use of GC-C agonists has been shown to improve abdominal symptoms of bloating, discomfort, and pain in patients with chronic idiopathic constipation and irritable bowel syndrome with constipation 1. GC-C is a transmembrane receptor protein that plays a crucial role in maintaining intestinal fluid homeostasis and mucosal integrity. When activated, GC-C catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), leading to chloride and bicarbonate secretion into the intestinal lumen and increasing intestinal fluid content.

Some key points to consider when using GC-C agonists include:

• Linaclotide is contraindicated in individuals with known or suspected mechanical GI obstruction 1
• Patients should be instructed to take linaclotide without food, at least 30 minutes before the first meal of the day 1
• The most common reasons for discontinuation of linaclotide are loss of efficacy and insurance coverage barriers, rather than adverse events 1
• GC-C agonists may be associated with diarrhea, but this is not a common reason for discontinuation 1

Overall, the use of GC-C agonists, such as linaclotide, is a highly effective treatment option for chronic idiopathic constipation, with a favorable safety profile and significant improvements in abdominal symptoms. As noted in the 2023 American Gastroenterological Association-American College of Gastroenterology clinical practice guideline, linaclotide is FDA-approved for the treatment of chronic idiopathic constipation at a dose of 72μg or 145μg daily 1.

From the FDA Drug Label

Linaclotide is structurally related to human guanylin and uroguanylin and functions as a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP) Linaclotide is a guanylate cyclase-C (G-CC) agonist

• Guanylate Cyclase-C (GC-C) is the target of linaclotide, and it functions by binding to GC-C and increasing the concentrations of cyclic guanosine monophosphate (cGMP) 2, 2.
• The mechanism of action of linaclotide involves the activation of GC-C, which stimulates the secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased intestinal fluid and accelerated transit.
• Linaclotide binds to GC-C and acts locally on the luminal surface of the intestinal epithelium.

From the Research

Guanylate Cyclase-C (GC-C) Overview

• Guanylate cyclase C (GC-C) is a transmembrane receptor expressed primarily on intestinal epithelial cells 3
• GC-C plays a crucial role in regulating physiological salt and water homeostasis in the intestine 3

Physiological Function of GC-C

• Activation of GC-C by its endogenous peptide ligands initiates cyclic guanosine monophosphate-dependent (cGMP) salt and water movement in the intestine 3
• GC-C regulates the composition of intestinal commensal microflora and suppresses bacterial infection and modulates colonic injury and inflammation 3

Therapeutic Applications of GC-C Ligands

• Therapeutic GC-C ligands, such as linaclotide, are used to treat constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation (CC) 4, 5, 6, 7
• Linaclotide, a GC-C agonist, increases intracellular cyclic guanosine monophosphate (cGMP), resulting in increased fluid secretion and gastrointestinal transit 4, 5, 6

Efficacy and Safety of Linaclotide

• Linaclotide has been shown to be effective in improving constipation, abdominal symptoms, and quality of life in patients with IBS-C and CC 4, 7
• The main adverse reaction of linaclotide is diarrhea, which is higher than that of the placebo in treating CC and IBS-C 7

Mechanism of Action of Linaclotide

• Linaclotide binds to GC-C receptors on intestinal epithelial cells, increasing intracellular cGMP and eliciting pharmacological effects locally in the gastrointestinal tract 5, 6
• Linaclotide has a low oral bioavailability and is stable in the gastrointestinal tract, allowing it to act locally without being absorbed into the bloodstream 5, 6