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Purinergic mechanisms in the control of gastrointestinal motility.

ABSTRACT: For many years, ATP and adenosine have been implicated in movement regulation of the gastrointestinal tract. They act through three major receptor subtypes: adenosine or P1 receptors, P2X receptors and P2Y receptors. Each of these major receptor types can be subdivided into several different classes and is widely distributed amongst various neurons, muscle types, glia and interstitial cells that regulate intestinal functions. Several key roles for the different receptors and their endogenous ligands have been identified in physiological and pharmacological studies. For example, adenosine acting at A(1) receptors appears to inhibit intestinal motility in various pathological conditions. Similarly, ATP acting at P2Y receptors is an important component of inhibitory neuromuscular transmission, acting as a cotransmitter with nitric oxide. ATP acting at P2X and P2Y(1) receptors is important for synaptic transmission in simple descending excitatory and inhibitory reflex pathways. Some P2Y receptor subtypes prefer uridine nucleotides over purine nucleotides. Thus, roles for UTP and UDP as enteric transmitters in place of ATP cannot be excluded. ATP also appears to be important for sensory transduction, especially in chemosensitive pathways that initiate local inhibitory reflexes. Despite this evidence, data are lacking about the roles of either adenosine or ATP in more complex motility patterns such as segmentation or the interdigestive migrating motor complex. Clarification of roles for purinergic transmission in these common, but understudied, motility patterns will depend on the use of subtype-specific antagonists that in some cases have not yet been developed.

SUBMITTER: Bornstein JC

PROVIDER: S-EPMC2486340 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Project description: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) (P2X(1-7), P2Y(2), P2Y(4), P2Y(6), P2Y(12) 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 (A(1), A(3), P2Y(12)) or excitatory (A(2), P2Y(1)) receptors modulate mechanosensitive 5-HT release. Excitatory (P2Y(1), other P2Y, P2X) or inhibitory (A(1), A(3)) receptors are involved in mechanically evoked secretory reflexes or "neurogenic diarrhea." Distinct neural (pre- or postsynaptic) and non-neural distribution profiles of P2X(2), P2X(3), P2X(5), P2Y(1), P2Y(2), P2Y(4), P2Y(6), or P2Y(12) receptors, and for some their effects on neurotransmission, suggests their role in GI secretomotor function. Luminal A(2b), P2Y(2), P2Y(4), and P2Y(6) receptors are involved in fluid and Cl(-), HCO(3) (-), K(+), or mucin secretion. Abnormal receptor expression in GI diseases may be of clinical relevance. Adenosine A(2a) or A(3) 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.

Project description:Treatments for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), functional dyspepsia, or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. Gastrointestinal symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation, and diarrhea. The focus of this review is on the potential for developing purinergic drugs for clinical trials to treat gastrointestinal symptoms. Purinergic receptors are divided into adenosine P1 (A(1), A(2A), A(2B), A(3)), ionotropic ATP-gated P2X ion channel (P2X(1-7)), or metabotropic P2Y(1,2,4,6,11-14) receptors. There is good experimental evidence for targeting A(2A), A(2B), A(3), P2X(7), and P2X(3) receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory diarrhea, and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X(7)R antagonist AZD9056 is in clinical trials for Crohn's disease. A(3) adenosine receptor drugs target inflammatory diseases (e.g., CF101, CF102). Dipyridamole, a nucleoside uptake inhibitor, is in trials for endotoxemia. Drugs for pain in clinical trials include P2X(3)/P2X(2/3) (AF-219) and P2X(7) (GSK1482160) antagonists and A(1) (GW493838) or A(2A) (BVT.115959) agonists. Iberogast is a phytopharmacon targeting purine mechanisms with efficacy in IBS and functional dyspepsia. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, functional dyspepsia, and inflammatory diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling.

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Purinergic mechanisms in the control of gastrointestinal motility.

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