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 (ISC = 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 M3 muscarinic ACh receptors (mAChRs) and, to a lesser extent, neuronal M1 mAChRs; however, AChR pharmacology has been plagued by a lack of good receptor subtype-selective compounds. Mice lacking M3 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.

Figure 1

Schematic representation of the intestinal epithelial Cl⁻ secretory pathway that is upregulated by ACh. The electrochemical gradient is established by the basolateral Na/K-ATPase pump; this allows entry of Na⁺, Cl⁻ and K⁺ through the basolateral membrane via the NKCC1 cotransporter; K⁺ is recycled through basolateral K⁺ channels, one of which is controlled by [Ca²⁺]_i, likely the intermediate conductance K⁺ channel (IK), and Cl⁻ is shunted to the apical membrane, where it exits into the lumen via the apical CFTR Cl⁻ channel and possibly also through an apical Ca²⁺-activated Cl⁻ channel (CaCC, designated Cl_Ca). For additional details, refer to Barrett and Keely (2000).

Figure 2

Intracellular regulation of intestinal epithelial Cl⁻ secretion by ACh (based on the secretory pathway depicted in Figure 1). G_q/11 α subunits (coupled to odd-numbered mAChRs) stimulate membrane phospholipid turnover by PLC. Inositol 1,4,5-trisphosphate (I[1,4,5]P₃) stimulates a rise in [Ca²⁺]_i; eventual conversion of IP₃ products to IP₄ by phosphatidylinositol kinases turns off Cl⁻ secretion, possibly by inhibiting Ca²⁺-activated Cl⁻ channels (Cl_Ca). DAG activates classical (e.g. PKCα) and novel (e.g. PKCɛ) isoforms of PKC; PKCα and/or PKCɛ may be required for initial stimulation of apical Cl⁻ secretion, but ultimately serve to downregulate this process through effects on ion transport molecules. Refer to the text for further details.