Muscarinic agonists and antagonists: effects on gastrointestinal function

Area of Science:

• Gastroenterology
• Pharmacology
• Molecular Biology

Background:

• Muscarinic agonists and antagonists are crucial for managing gastrointestinal (GI) disorders linked to salivary secretion issues or altered GI smooth muscle motility.
• The M₃ muscarinic receptor is predominant in salivary, gastric, and pancreatic glands for exocrine secretion, with a minor M₁ contribution.
• GI smooth muscle predominantly expresses M₂ and M₃ muscarinic receptors, with M₂ receptors being at least four times more abundant than M₃ receptors.

Purpose of the Study:

• To elucidate the specific roles and mechanisms of muscarinic receptor subtypes (M₁, M₂, M₃) in regulating gastrointestinal (GI) functions, including exocrine secretion and smooth muscle contraction.
• To investigate the apparent discrepancy between the high M₂ receptor expression in GI smooth muscle and the observed M₃-mediated antagonism of contraction.

Main Methods:

• Review and synthesis of existing literature on muscarinic receptor expression and function in the GI tract.
• Analysis of signaling pathways and physiological responses associated with M₁, M₂, and M₃ receptor activation and antagonism in GI tissues.

Main Results:

• Exocrine secretion in the GI tract is primarily mediated by the M₃ muscarinic receptor, with some M₁ involvement.
• Despite higher M₂ receptor expression in GI smooth muscle, contraction is predominantly antagonized via M₃ receptors.
• The contractile role of M₂ receptors in GI smooth muscle is conditional, depending on M₃ receptor activity; M₃ antagonism abolishes M₂-mediated responses.

Conclusions:

• The M₃ muscarinic receptor plays a critical role in both GI exocrine secretion and smooth muscle contraction.
• M₂ muscarinic receptor function in GI smooth muscle contraction is secondary to M₃ receptor activity.
• Observed tissue selectivity of some M₃ antagonists may stem from interactions with non-muscarinic targets.