Purinergic receptors and gastrointestinal secretomotor function

Open Access
Publisher Website
Google Scholar
Abstract
Secretomotor reflexes in the gastrointestinal (GI) tract are important in the lubrication and movement of digested products, absorption of nutrients, or the diarrhea that occurs in diseases to flush out unwanted microbes. Mechanical or chemical stimulation of mucosal sensory enterochromaffin (EC) cells triggers release of serotonin (5-HT) (among other mediators) and initiates local reflexes by activating intrinsic primary afferent neurons of the submucous plexus. Signals are conveyed to interneurons or secretomotor neurons to stimulate chloride and fluid secretion. Inputs from myenteric neurons modulate secretory rates and reflexes, and special neural circuits exist to coordinate secretion with motility. Cellular components of secretomotor reflexes variably express purinergic receptors for adenosine (A1, A2a, A2b, or A3 receptors) or the nucleotides adenosine 5′-triphosphate (ATP), adenosine diphosphate (ADP), uridine 5′-triphosphate (UTP), or uridine diphosphate (UDP) (P2X1-7, P2Y2, P2Y4, P2Y6, P2Y12 receptors). This review focuses on the emerging concepts in our understanding of purinergic regulation at these receptors, and in particular of mechanosensory reflexes. Purinergic inhibitory (A1, A3, P2Y12) or excitatory (A2, P2Y1) receptors modulate mechanosensitive 5-HT release. Excitatory (P2Y1, other P2Y, P2X) or inhibitory (A1, A3) receptors are involved in mechanically evoked secretory reflexes or “neurogenic diarrhea.” Distinct neural (pre- or postsynaptic) and non-neural distribution profiles of P2X2, P2X3, P2X5, P2Y1, P2Y2, P2Y4, P2Y6, or P2Y12 receptors, and for some their effects on neurotransmission, suggests their role in GI secretomotor function. Luminal A2b, P2Y2, P2Y4, and P2Y6 receptors are involved in fluid and Cl-, HCO3 -, K+, or mucin secretion. Abnormal receptor expression in GI diseases may be of clinical relevance. Adenosine A2a or A3 receptors are emerging as therapeutic targets in inflammatory bowel diseases (IBD) and gastroprotection; they can also prevent purinergic receptor abnormalities and diarrhea. Purines are emerging as fundamental regulators of enteric secretomotor reflexes in health and disease.