Purinergic drug targets for gastrointestinal disorders
Introduction
Purinergic receptors, which are widely distributed in the gastrointestinal tract, mediate signalling in enteric glia, the enteric nervous system and at the neuromuscular junction [1, 2, 3, 4, 5]. Figure 1 is a schematic showing the characterisation of purinoceptors in the gut. There are three classes of purinoceptors: seven subtypes of ligand-gated ion channels (P2XRs), eight subtypes of nucleotide-activated G protein-coupled receptors (P2YRs) and four subtypes of G protein-coupled adenosine receptors (ARs, also designated P1 receptors). Our knowledge is based primarily on animal data, although recent studies described here focus more on purinergic signalling in the human gut. Purinergic receptors are key components of, and function at all levels of enteric neural reflexes and in both intrinsic and extrinsic neural pathways. Furthermore, purinergic signalling is an important regulator in activation and trafficking of immune/inflammatory cells [6, 7, 8]. Activation of P2Rs generally boosts the immune response, while ARs tend to suppress it. Therefore, it is not surprising that there is a great deal of interest in further understanding the role of purines in pathogenic mechanisms and their therapeutic potential in gastrointestinal diseases, as reviewed [9, 10].
Section snippets
Medicinal chemistry of purinergic receptors
The X-ray crystallographic structures of ARs and P2YRs are aiding the design of novel ligands by rational structure-based approaches [11]. However, most commonly used AR ligand tools were discovered by empirical approaches (Figure 2, [3, 12••]). Cl-ENBA (number 3 in Figure 2) is a more selective A1AR agonist for in vivo use than 1 and 2 [13]. CGS21680 (not shown) is an A2AAR agonist in rat, but has substantial human (h) A3AR affinity [14]. Potent A2AAR agonist ATL-313 5 attenuates colitis in
P2X7R in inflammatory bowel disease (IBD)
IBD includes two main clinical forms, ulcerative colitis (UC) and Crohn's disease (CD). Under inflammatory conditions, ATP is released. P2X7R is preferentially expressed by immune cells, particularly macrophages, which, when activated, release inflammatory cytokines, mediate inflammasome formation and enhance phagocytosis. Reviews discussing the role of P2X7R in IBD are available [21, 22].
P2X7R is involved in colonic motor dysfunction associated with bowel inflammation. P2X7R modulates the
Ulcerative colitis (UC)
Extracellular ATP mediates inflammatory responses in colitis via P2X7R signalling [29]. Colitis differentially affects P2X7R-expressing enteric neurons based on their chemical codes [30]. P2X7R activation also triggers mucosal regulatory T cell death [26]. P2X7R antagonist A438079 35 down-regulates the production of pro-inflammatory cytokines in colonic tissues, and attenuates murine colitis, indicating P2X7R-dependent triggering of immune responses during colitis [29].
Extracellular ATP
Crohn's disease (CD)
The inflammasome is a multiprotein complex belonging to the innate immune system and activation of P2X7R results in secretion of inflammatory cytokines. A significant difference in expression of the inflammasome in CD patients was observed, with increased expression of interleukin-1β and activation of the P2X7R [40]. There is overexpression of P2X7R in the inflamed mucosa in CD, suggesting that P2X7R may be a novel target for CD [41].
A randomized placebo-controlled, double blind, Phase IIa
Purinergic signalling pathways in enteric glia and neurons as a target for IBD and motility disorders
Emerging evidence suggests that reactive enteric glia or alterations in glia induced by inflammation, infection or surgical intestinal manipulation/trauma may contribute to disturbed motility in intestinal diseases including postoperative ileus, GI symptoms in Parkinson's Disease (i.e. constipation), idiopathic severe slow transit constipation, diverticular disease, IBD, infectious colitis, and necrotizing enterocolitis. Common features in these diseases that suggest a role for glia in
Motility disorders
A review, focussed on the physiological mechanisms responsible for nerve-mediated purinergic relaxation, provides a functional basis for clinical and pharmacological studies on defective GI motility [50].
The phytoalkaloid berberine is traditionally used to treat GI motility disorders, but it is not used as a treatment strategy in the USA. In a recent study, berberine was shown to decrease the amplitude and frequency of pacemaker potentials via ATP sensitive K+ channels [51]. The purinergic fast
Irritable bowel syndrome (IBS)
Diarrhoea-predominant IBS is characterised by abdominal pain and increased expression of P2Y1R and P2Y2R in the rectosigmoid mucosa of IBS patients [56]. P2Y2R expression may be correlated with abdominal pain. Visceral hypersensitivity is often seen in IBS. It has been suggested that P2X7R of rat dorsal root ganglia may play a role in the transmission of the nociceptive signal [57]. Emerging evidence suggests that electroacupuncture may downregulate the expression of the P2X3R and ease the
Gut pain
ATP release from mucosal epithelial cells, to activate P2X3R expressed on nociceptive primary afferent sensory nerve endings in the submucosa, was proposed to relay messages via the spinal cord to the conscious pain centres in the brain [59]. P2X3R antagonists and anti-P2X3R antibodies are being explored as therapeutic agents against colic and colitis pain [32, 60].
Gastroesophageal reflux disease
Roles for adenosine, ATP and UTP in the pathogenesis of gastroesophageal reflux disease symptoms have been considered [61]. Purinergic receptors have been demonstrated in various species, including humans, and there is recent evidence to implicate a role for P2Y2 and A2ARs in esophageal hypersensitivity.
Clinical studies have shown that adenosine contributes to esophageal mechanical hypersensitivity and non-cardiac chest pain originating in the esophagus [62]. Stimulation of A2AAR induces
Gut cancer
High expression of the ecto-nucleotidase CD39 occurs in malignant epithelial cells of human rectal adenocarcinoma [64]. P2X7R activation mediated inflammatory responses and suppressed colitis-associated cancer development. Inactivation of the purinergic P2X7R dampens inflammation in a colitis model, but increases tumor incidence in a mouse colitis-associated cancer model [65•]. Therefore, the use of P2X7R antagonists to treat IBD should be approached with some caution.
The protein kinase
Gut infection
Aged mice are less able to deal with inflammation from Candida albicans infection due to lower gut density of A2AAR, which is an inflammation stop signal [68].
Purinergic receptors have been proposed to be key mediators of human immunodeficiency virus type 1 (HIV-1) infection and inflammation [69]. Chronic HIV-1 infection leads to a decrease in the integrity of the mucosal epithelial barrier, bacterial translocation and high bacterial lipopolysaccharide levels in HIV-infected individuals. A
Conclusions
Antagonists of P2XRs, and P2X7R and P2X3R, in particular, are potential therapeutic targets for treating IBD, IBS and motility disorders. Other targets include A2AAR agonists, A2BAR modulators, A3AR agonists and P2Y2R antagonists. Furthermore, modulation of the levels of endogenous purinoceptor agonists indirectly through enzymes and transporters can provide benefit in gastrointestinal disorders. MicroRNAs can also tune the levels of purinergic mediator proteins. Medicinal chemistry is
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
We acknowledge support from the NIH Intramural Research Program to K.A. Jacobson; NIH NIDDK grants DK093499 and DK113943 and Office of Research & Dean's Bridge Grant, College of Medicine at The Ohio State University to F.L. Christofi.
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