Autonomic nervous system and secretion across the intestinal mucosal surface

Abstract

Chloride secretion is important because it is the driving force for fluid movement into the intestinal lumen. The flow of accumulated fluid flushes out invading micro-organisms in defense of the host. Chloride secretion is regulated by neurons in the submucosal plexus of the enteric nervous system. Mechanosensitive enterochromaffin cells that release 5-hydroxytryptamine (5-HT) and activate intrinsic afferent neurons in the submucosal plexus and initiate chloride secretion. Mechanical stimulation by distention may also trigger reflexes by a direct action on intrinsic afferent neurons. Dysregulation of 5-HT release or altered activity of intrinsic afferents is likely to occur in states of inflammation and other disorders.

Figure 1

A. Crypt cell. Cl⁻ secretion through cystic fibrosis transmembrane regulator Cl⁻ channels (CFTR) or other Cl⁻ channels (CIC-2 and CLCA). Cl- secretion through ion channels is dependent on the electrochemical driving forces. (See test page 2). B. Crypt cell with intracellular Gαq signaling for mobilization of Ca⁺² when acetylcholine binds to M3 receptors, and with Gαs signaling pathways for elevation of cAMP by VIP binding to VPAC1 receptors. C. Enterochromaffin cell model (human BON cell). Mechanical stimulation by mucosal stroking or rotational shaking (MS), releases adenosine triphosphate, (ATP). It exists t he cell and is converted to adenosine di-phosphate (ADP). ADP activates P2Y1 receptors coupled to Gaq signaling and 5-HT release. 5-HT activates 5-HT receptors on intrinsic afferents and neurotransmission through secretomotor neurons release VIP or acetylcholine. Inostitol triphosphate (IP3), phospholipase C (PLC), diacylglycerol (DAG), protein kinase C and intracellular mobilization of intracellular Ca⁺², adelylyl cyclase (AC), protein kinase A (PKA).

Figure 2

Reflex activity stimulated by mucosal stroking the intestinal lining or rotational shaking of cultured enterochromaffin derived cell line, BON. The mechanotransduction pathway is initiated by 5-HT released from enterochromaffin cells which activates a reflex arc within the submucosal plexus. P2Y1 receptors are on enterochromaffin cells. P2Y1 receptors are down stream in neural pathways and found on cholinergic secretomotor neurons in the guinea pig colon and VIP secretomotor neurons in the ileum. Thus the mechanosensitive pathway triggered by mucosal stroking involves release of 5-HT and activation of intrinsic afferents that do not express P2Y1 receptors. This may alter the excitability of secretomotor neurons. In contrast, stretch is expected to activate submucosal afferents directly without the need for 5-HT. Secretory reflexes are shown to go through the submucosal plexus. Mechanically evoked 5-HT can also activate myenteric neurons via 5-HT3 receptors to initiate long reflexes.