Enteric acetylcholine synthesis and signaling pathway

The enteric acetylcholine synthesis and signaling pathway is the primary excitatory neurotransmitter system within the enteric nervous system (ENS), responsible for regulating gastrointestinal motility, secretion, and local blood flow (Furness, 2006). Acetylcholine (ACh) is synthesized by the enzyme choline acetyltransferase (ChAT) and stored in vesicles by the vesicular acetylcholine transporter (VAChT) before being released into the synapse (Harrington et al., 2010). Once released, ACh binds to nicotinic receptors (nAChRs) for rapid interneuronal communication or muscarinic receptors (primarily M2 and M3) on smooth muscle and epithelial cells to stimulate contraction and fluid secretion (Hirota & McKnight, 2007). The signaling is terminated by acetylcholinesterase (AChE), which hydrolyzes ACh in the synaptic cleft. Dysregulation of this pathway is central to the pathophysiology of various gastrointestinal disorders, including achalasia, gastroparesis, and irritable bowel syndrome (IBS) (Galligan, 2002). Pharmacological modulation involves the use of AChE inhibitors to enhance signaling or muscarinic antagonists to alleviate hypermotility, though these therapies are often limited by systemic side effects such as bradycardia or dry mouth (Tack et al., 2006; Broad & Sanger, 2013).

Other names

Enteric cholinergic systemIntestinal cholinergic signalingACh signaling in the ENSEnteric cholinergic pathway

Acetylcholinesterase inhibition to increase synaptic acetylcholine; Antagonism of muscarinic receptors to inhibit smooth muscle contraction; Agonism of muscarinic receptors to stimulate motility and secretion; Inhibition of vesicular acetylcholine release.