Cholinergic regulation of epithelial ion transport in the mammalian intestine

Abstract

Acetylcholine (ACh) is critical in controlling epithelial ion transport and hence water movements for gut hydration. Here we review the mechanism of cholinergic control of epithelial ion transport across the mammalian intestine. The cholinergic nervous system affects basal ion flux and can evoke increased active ion transport events. Most studies rely on measuring increases in short-circuit current (I SC ¼ active ion transport) evoked by adding ACh or cholinomimetics to intestinal tissue mounted in Ussing chambers. Despite subtle species and gut regional differences, most data indicate that, under normal circumstances, the effect of ACh on intestinal ion transport is mainly an increase in Cl -secretion due to interaction with epithelial M 3 muscarinic ACh receptors (mAChRs) and, to a lesser extent, neuronal M 1 mAChRs; however, AChR pharmacology has been plagued by a lack of good receptor subtype-selective compounds. Mice lacking M 3 mAChRs display intact cholinergically-mediated intestinal ion transport, suggesting a possible compensatory mechanism. Inflamed tissues often display perturbations in the enteric cholinergic system and reduced intestinal ion transport responses to cholinomimetics. The mechanism(s) underlying this hyporesponsiveness are not fully defined. Inflammation-evoked loss of mAChR-mediated control of epithelial ion transport in the mouse reveals a role for neuronal nicotinic AChRs, representing a hitherto unappreciated braking system to limit ACh-evoked Cl -secretion. We suggest that: i) pharmacological analyses should be supported by the use of more selective compounds and supplemented with molecular biology techniques targeting specific ACh receptors and signalling molecules, and ii) assessment of ion transport in normal tissue must be complemented with investigations of tissues from patients or animals with intestinal disease to reveal control mechanisms that may go undetected by focusing on healthy tissue only.

Effect of Milk Formula Protein Content on Intestinal Barrier Function in a Porcine Model of LBW Neonates

“…Indeed, the jejunum of HP piglets did not respond to carbachol (cholinergic agonist) or VIP as opposed to MF and AP piglets while in the ileum they did respond to VIP when MF and AP piglets did not. Such reduced response of the gut to cholinergic stimulation has been observed in various cases of gut dysfunction: electrolyte secretion in response to cholinomimetics was reduced in mice with T cell-driven enteropathies or rats infected with nematodes as a model of colitis (31); the smooth muscle contractile response to cholinergic stimulation was also reduced in the inflamed intestine (32). In the former study, altered acetylcholine metabolism 8 (increase AChE expression and activity, decreased packaging and exocytosis of acetylcholine, alteration of ChAT expression…) was involved (31).…”

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

“…However, it is still not clear whether these effects of EGC are direct effects on enterocytes or indirect effects via activation or inactivation of enteric neurons. It has been speculated that a possible effect of EGC could be via stimulation of enteric neurons, since neuronal effectors such as acetylcholine, vasoactive intestinal peptide, and nitric oxide are known key regulators of IEB (26,38). However, there is upcoming evidence showing that EGC directly regulate IEB.…”

“…It is well known that neuronal effector proteins are involved in the regulation of IEB. Acetylcholine, vasoactive intestinal peptide, and nitric oxide influence mucosal blood flow, lymphocyte migration, mucus secretion, and resorption of nutrients (26,39). Overall, it has been demonstrated that activation of enteric neurons results in a stabilization of IEB.…”

Endurance swimming stimulates transepithelial calcium transport and alters the expression of genes related to calcium absorption in the intestine of rats

“…However, previous investigation suggested that the voltage-gated K ϩ channels regulated membrane potential, which was, in turn, important for the Na ϩ -dependent absorption of glucose and amino acids in the small intestine (37). Although the physiological functions of most swimming-altered genes have never been investigated, a number of genes are possibly involved in water and electrolyte homeostasis, such as cholinergic receptor, kallikrein-kinin, neuropeptide Y, aquaporin, renin, vasopressin, and galanin receptor (2,12,23,25,35,50). These genes could partially explain changes in water and electrolyte metabolism during exercise training (3).…”