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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Purinergic Signalling (2008) 4:213–236 DOI 10.1007/s11302-008-9104-4 ORIGINAL ARTICLE Purinergic receptors and gastrointestinal secretomotor function Fievos Leontiou Christofi Received: 17 May 2007 /Accepted: 7 April 2008 /Published online: 5 July 2008 # Springer Science + Business Media B.V. 2008 Abstract Secretomotor reflexes in the gastrointestinal (GI) (A2, P2Y1) receptors modulate mechanosensitive 5-HT tract are important in the lubrication and movement of release. Excitatory (P2Y1, other P2Y, P2X) or inhibitory digested products, absorption of nutrients, or the diarrhea (A1,A3) receptors are involved in mechanically evoked that occurs in diseases to flush out unwanted microbes. secretory reflexes or “neurogenic diarrhea.” Distinct neural Mechanical or chemical stimulation of mucosal sensory (pre- or postsynaptic) and non-neural distribution profiles enterochromaffin (EC) cells triggers release of serotonin of P2X2, P2X3, P2X5, P2Y1, P2Y2,P2Y4,P2Y6,orP2Y12 (5-HT) (among other mediators) and initiates local reflexes receptors, and for some their effects on neurotransmission, by activating intrinsic primary afferent neurons of the suggests their role in GI secretomotor function. Luminal submucous plexus. Signals are conveyed to interneurons or A2b, P2Y2, P2Y4, and P2Y6 receptors are involved in fluid - - + secretomotor neurons to stimulate chloride and fluid and Cl , HCO3 ,K , or mucin secretion. Abnormal receptor secretion. Inputs from myenteric neurons modulate secre- expression in GI diseases may be of clinical relevance. tory rates and reflexes, and special neural circuits exist to Adenosine A2a or A3 receptors are emerging as therapeutic coordinate secretion with motility. Cellular components of targets in inflammatory bowel diseases (IBD) and gastro- secretomotor reflexes variably express purinergic receptors protection; they can also prevent purinergic receptor for adenosine (A1, A2a, A2b, or A3 receptors) or the abnormalities and diarrhea. Purines are emerging as nucleotides adenosine 5′-triphosphate (ATP), adenosine fundamental regulators of enteric secretomotor reflexes in diphosphate (ADP), uridine 5′-triphosphate (UTP), or health and disease. uridine diphosphate (UDP) (P2X1-7, P2Y2, P2Y4, P2Y6, P2Y12 receptors). This review focuses on the emerging Keywords Chloride secretion . Gastrointestinal tract . concepts in our understanding of purinergic regulation at Enterochromaffin cells . 5-HT release . Submucous plexus . these receptors, and in particular of mechanosensory Epithelial cells . Mucosal reflex . Mechanosensitivity. reflexes. Purinergic inhibitory (A1,A3, P2Y12) or excitatory Purinergic receptors . P2X receptors . P2Y receptors . Adenosine receptors Abbreviations F. L. Christofi 5-HT serotonin Department of Anesthesiology, The Ohio State University, ADA adenosine deaminase Columbus, OH 43210, USA AK adenosine kinase F. L. Christofi (*) AR-C69931MX or N6-(2-methylthioethyl)-2-(3,3, College of Medicine and Public Health, cangrelor 3-trifluoropropylthio)-βγ- The Ohio State University, dichloromethylene-ATP 226 Tzagournis Medical Research Facility, ATP adenosine 5′-triphosphate 420 West 12th Avenue, 2+ - Columbus, OH 43210, USA CaCC Ca -dependent Cl channels e-mail: [email protected] cAMP 3′,5′-cyclic adenosine monophosphate 214 Purinergic Signalling (2008) 4:213–236 CFTR cystic fibrosis conductance Structural or functional changes in the enteric nervous transmembrane regulator system (ENS), in neurotransmitters, signaling pathways, or ChaT choline acetyltransferase other components of enteric neural reflexes may be the EC enterochromaffin cell basis for the pathogenesis of disturbances in gut motor ENaC amiloride-sensitive epithelial Na+ function. channels The current review will focus primarily on the role of ENS enteric nervous system purines in secretomotor function in the GI system. The EPAN extrinsic primary afferent neuron enterochromaffin–neural circuit–epithelial reflex pathway is GI gastrointestinal tract our target for understanding secretomotor function in the IBD inflammatory bowel diseases intestinal tract. All cellular components of mucosal reflexes IPAN intrinsic primary afferent neuron express purinergic receptors, and this review will focus on -ir immunoreactivity these receptors, their distribution, and function in mucosal Isc short-circuit current indicative of reflexes and secretomotor function in the GI tract. The chloride secretion enteric neural circuits and cellular components involved in 2MeSADP 2-methylthioADP neurosecretory reflexes will first be briefly reviewed. A MRS2279 2-chloro-N6-methyl-(N)- brief overview and basic knowledge of purinoceptor methanocarba-2′-deoxyadenosine- classification, pharmacology, receptor ligands and their 3′5′-bisphosphate selectivity is necessary in order to understand the concepts MRS2179 2′-deoxy-N6-methyladenosine- forwarded in this review. Emerging concepts will be 3′5′-bisphosphate reviewed in our understanding of purinergic regulation in MRS2211 6-(2′-chloro-5-nitro-azophenyl)- mucosal reflexes, with particular emphasis on enterochro- pyridoxal-α5-phosphate maffin cells (EC), mucosal reflexes, receptor distribution, MRS2567 1.2-di-(4-isothio-cyanatophenyl) and luminal P2 receptors involved in epithelial ion transport ethane and fluid secretion. In addition, we review recent findings NBTI S-(p-nitrobenzyl)-6-thioinosine on purinergic regulation of gastric secretions, and in NPY neuropeptide Y relation to gastric mucosal protection. Our review would PLC phospholipase C not be complete without a very brief description of the PPADS pyridoxal phosphate-6-azo(benzene- emerging role of purinergic receptors as therapeutic targets 2,4-disulfonic acid) tetrasodium salt in IBD [2] or implications of purine receptor abnormalities R receptor (up- or downregulation) in GI diarrhea diseases. The reader SP substance P is also referred to more general reviews on purinergic VIP vasoactive intestinal peptide signaling [12], GI secretomotor function and dysfunction [25, 26], epithelial secretion, and hepatobiliary function [92]. Other relevant reviews include adenosine neuro- modulation [20], purines in mechanosensory signaling Introduction [26], ATP as a sensory transmitter [6], and P2Y1 receptors in secretomotor function [113], or P2X receptors as Gastrointestinal (GI) secretions in coordination with motil- potential targets in IBS [40]. ity are important in digestion of food particles, lubrication, nutrient absorption, regulation of pH and solute concentra- tion, and elimination of waste products. Diarrhea occurs in Enterochromaffin–neural–epithelial reflex pathways GI diseases to flush out noxious chemicals or unwanted microbes. Intestinal chloride secretion provides a driving The secretory reflex is composed of sensory EC cells, force for fluid movement and obligate transport of water intrinsic primary afferent neurons (IPANs), various inter- into the lumen. Under normal circumstances, mucosal neurons, secretomotor neurons, interplexus neurons for chloride secretion is very low, but can reach extraordinary coordinating secretion and motility or for secretomotor rates when challenged by enterotoxins or various secreto- function [11], and the epithelial cells involved in ion gogues. Hallmarks of enteric infections or inflammatory transport and fluid secretion in the gut lumen (Fig. 1). bowel diseases (IBD) are malaise and diarrhea; the other Luminal stimulation by nutrients, changes in pH, mechan- extreme is constipation that occurs in patients with ical forces, changes in solute concentration, luminal idiopathic constipation, constipation-predominant irritable irritants, or invading enteropathogenic microorganisms will bowel syndrome (IBS), or opioid-induced constipation. activate the EC cells to secrete serotonin (5-HT) among Purinergic Signalling (2008) 4:213–236 215 SMALL INTESTINE 5HT SECRETOMOTOR IPANS VASOMOTOR NON-VASOMOTOR ACh,SP,Glu,CGRP MYENTERIC CM SUBMUCOSAL 5HT3? 5HT4 P2Y1 NK1/ VIP NK3 AXON REFLEX? P2Y1 CHAT/CALB VIP/cAMP VIP E VIP/cAMP(-) SP CHAT/CALRET 5HT CHAT/NPY NK1 CHAT(-) VPAC VIP M3 ACH VIP ACH EC M3 VPAC M3 Cl - EPITHIELIAL Cl SECRETION DISTORTION Cl - Cl - Fig. 1 Generic intestinal secretory reflex based on guinea pig cAMP (-) and may be further subdivided into VIP/cAMP/A2aRs and intestine. Neural reflex pathway regulating secretion includes EC VIP/cAMP/A2aR (-). Cholinergic neurons are ChAT/calretinin sensory cells that release 5-HT to activate IPANS projecting to the (CALRET), CHAT/NPY, CHAT (-). Mechanical distortion such as mucosa, to submucous ganglia, and to myenteric ganglia. IPANS brush stroking the mucosa is one stimulus for activation of the reflex. synapse with several types of cholinergic (CHAT) and vasoactive Myenteric secretomotor neurons project to the mucosa as well. CGRP intestinal peptide (VIP) secretomotor neurons and release acetylcholine calcitonin gene-related peptide, EC enterochromaffin cells, 5-HT 5- (ACh) at muscarinic receptors (M3) and VIP at VIP receptors hydroxytryptamine, NK1 neurokinin-1, NPY neuropeptide Y, SP (VPACRs) on epithelial cells, or arterioles. VIP neurons are subdivided substance P, A2aRs adenosine A2a receptors. (Modified from [25]by according to their ability to generate cAMP as VIP/cAMP (+) and VIP/ permission) other mediators to trigger secretomotor reflexes leading to decoded and integrated in the cell soma and then relayed chloride, bicarbonate, potassium, mucin,
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