INVITED REVIEWControl of epithelial transport via luminal P2 receptors - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:34 |只看该作者 |倒序浏览 |打印

作者：JensLeipziger作者单位：Department of Physiology, The Water and Salt ResearchCenter, Aarhus University, 8000 Aarhus C, Denmark
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      【摘要】
   P2 membrane receptors are specificallyactivated by extracellular nucleotides like ATP, ADP, UTP, and UDP. P2receptors are subdivided into metabotropic P2Y and ionotropic P2Xreceptors. They are expressed in all tissues and induce a variety ofbiological effects. In epithelia, they are found in both thebasolateral and the luminal membranes. Their widespread luminalexpression in nearly all transporting epithelia and their effect ontransport are summarized. The P2Y 2 receptor is a prominentluminal receptor in many epithelia. Other luminal P2 receptors includethe P2X 7, P2Y 4, and P2Y 6 receptors.Functionally, luminal P2Y 2 receptor activation elicitsdifferential effects on ion transport. In nearly all secretoryepithelia, intracellular Ca 2  concentration-activated ionconductances are stimulated by luminal nucleotides to induceCl, K  , or HCO 3 − secretion.This encompasses respiratory and various gastrointestinal epithelia ortissues like the conjunctiva of the eye and the epithelium of sweatglands. In the distal nephron, all active transport processesappear to be inhibited by luminal nucleotides. P2Y 2 receptors inhibit Ca 2  and Na absorption andK secretion. Commonly, in all steroid-sensitive epithelia(lung, distal nephron, and distal colon), luminal ATP/UTP inhibitsepithelial Na channel-meditated Na absorption. ATP is readily released from epithelial cells onto theirluminal aspect, where ecto-nucleotidases promote their metabolism. Adenosine generated by the action of 5'-nucleotidase may elicit furthereffects on ion transport, often opposite those of ATP. ATP release fromepithelia continues to be poorly understood. Integrated functionalconcepts for luminal P2 receptors are suggested: 1 ) luminalP2 receptors are part of an epithelial "secretory" defensemechanism; 2 ) they may be involved in the regulation of cellvolume when transcellular solute transport is out of balance; 3 ) ATP and adenosine may be important autocrine/paracrineregulators mediating cellular protection and regeneration afterischemic cell damage; and 4 ) ATP and adenosine havebeen suggested to mediate renal cyst growth and enlargement inpolycystic kidney disease. 7 z, d( X7 i- x5 b, [
      【关键词】 PY PX chloride secretion sodium absorption epithelial sodiumchannel potassium secretion9 G' n1 G: Z) i  o% E
   INTRODUCTION! Y2 P( G+ ^: f* M  Y6 [6 K

EPITHELIAL TRANSPORT IS A regulatedphenomenon involving a large number of hormones and local agonists thatusually bind to their respective transmembrane receptors on thebasolateral membrane. Consequently, this influences intracellularsignaling processes involved in downstream regulation of transportproteins in either membrane domain. In addition, epithelial transportcan also be influenced by agonists present in the luminal compartment( 25, 125, 139 ). This has led to the hypothesis that theluminal membrane contains functionally important hormone receptors.Obviously, this concept has met with some resistance, because thesource of luminal agonists in particular is often uncertain. Given the fact that many epithelia must be considered "leaky," it can be adifficult task to investigate the hypothesis of luminal membrane receptors. It must be considered whether leakage of a "luminally" active substance may have occurred and whether the receptor site isactually on the basolateral membrane. Nonetheless, the use ofimmunocytochemistry and sided perfusion of high-resistance epithelia,like the collecting duct, has unequivocally demonstrated the existenceof luminal membrane receptors and defined some important aspects oftheir biological function ( 34, 125 ). Certainly, the mostconvincing evidence comes from studies in which the same agonist leadsto differential effects when applied to either the luminal orbasolateral side of the epithelium ( 54, 58, 82, 125 ). Oneprominent and well-established example of the control of epithelialtransport via a luminal agonist and its corresponding luminal receptoris guanylin. This intestinal peptide hormone binds to the luminalguanylate cyclase receptor to stimulate cGMP elevations andsubsequently G kinase II-mediated CFTR activation and Cl secretion ( 27 ). The guanylate cyclase receptor is also the target for Escherichia coli heat-stable enterotoxin thatmediates severe secretory diarrhea ( 26 ). For the mammaliannephron, a number of luminal agonists, such as PGE 2 ( 125 ), vasopressin ( 52 ), or ANG II( 104 ), have been described. Significant attention has recently focused on luminal ANG II and luminal AT 1 receptors. Remarkably high intratubular proximal ANG II concentrationscould be identified and are apparently generated by the proximal tubule itself. Luminal ANG II was shown to regulate Na andHCO 3 − absorption in the proximal and distal tubule,and thus ANG II obviously also travels along with the tubular fluid( 104 ).

This review focuses attention on one specific family of receptors,namely, those activated by extracellular nucleotides like, e.g., ATP,ADP, UTP, or UDP. These P2 or purinergic receptors have come to theawareness of almost every researcher in biology, because they areubiquitously expressed and are involved in a myriad of differentcellular functions ( 113 ). Mammalian P2 receptors aresubdivided into metabotropic (G protein-coupled) P2Y (P2Y 1, P2Y 2, P2Y 4, P2Y 6,P2Y 11, P2Y 12, and P2Y 13 ) andionotropic P2X (P2X 1-7 and P2XM) receptors ( 28, 113, 151, 161 ). One prominent feature of P2 receptors is theirextraordinarily frequent expression, especially in the luminal membraneof epithelia. Extracellular luminal nucleotides have been shown to beprominent regulators of ion transport. The widespread epithelial P2receptor expression is the reason for summarizing the present state ofknowledge. This review tries to comprehensively summarize the evidencefor luminal P2 receptors in intact epithelia and their functional effects on the various transport processes. More elaborate attention will be directed toward the mammalian nephron, and finally some integrative functional implications for luminal P2 receptors will be discussed.
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THE DISCOVERY OF LUMINAL P2 RECEPTORS
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Possibly the first experimental description of a luminal P2receptor-mediated effect was documented in 1969, when Kohn et al.( 65 ) investigated the transmural potential in the small intestine and showed that luminal (and basolateral) ATP stimulated aserosal positive-voltage change. The authors concluded that thisreflected "stimulation of ion transport" but assumed an"intracellular action of ATP." They speculated that "this mightrepresent a direct stimulation of the electrogenic sodium pump at theserosal pole of the epithelial cells" but were puzzled by the factthat they failed to demonstrate a significant depression of theresponse in Mg 2  -free saline, although there is an absoluterequirement for Mg 2  by the ATPase system. At that time, P2receptors were yet to be discovered. Starting in the early 1990s, thework of a number of groups has led to a nearly comprehensive cloningand characterization of the large and diverse family of P2 receptors( 113 ). Interestingly, the characterization of the luminalenterocyte P2 receptors in the small intestine still remains poorlydefined, except that the P2Y 4 receptor seems to be onepossible candidate ( 15 ).( x3 u1 \/ ~) Y' s6 n

After the recognition of the P2 receptor family, it was the work ofWong ( 159 ) that led to the discovery that the isolated perfused rat epididymis responds to luminal ATP with Cl secretion, e.g., movement of NaCl and H 2 O into the ductallumen. Because no effect was detected with basolateral ATP, the authors concluded that a luminal P2 receptor is responsible for this effect. Obviously, the most important question was to establish the source ofluminal ATP in the epididymis. The authors suggested that the high ATPconcentrations present in the spermatozoa could be released, therebystimulating Cl secretion and fluidity of the localenvironment and thus facilitating sperm transport. Evidence for this isstill pending, but present theories follow these lines and propose thatextracellular ATP in general is a local paracrine/autocrine regulator( 42 ). Thus the epididymis was the first intact epithelialtissue in which luminal P2 receptors were described, leading subsequentinvestigators to describe the effect of luminal ATP or othernucleotides in nearly all epithelial tissues. Noteworthy here is anearly study by Simmons ( 137 ), who in 1981 described aluminal ATP-stimulated effect on Cl secretion andcorrectly assumed that P2 receptors were localized at "each of thecellular membranes of this epithelium." Table 1 summarizes the epithelial organsexpressing luminal P2 receptors, the most likely P2 receptor subtype,and the regulated ion transport process.5 M- j4 x# K, c6 K# r: E
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Table 1. List of luminal P2 receptors in transporting mammalian epithelia
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LUMINAL P2 RECEPTORS IN RESPIRATORY EPITHELIUM
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Not long after the results in epididymis appeared( 159 ), the respiratory epithelium was discovered to be aremarkably rich source of the expression of luminal P2 receptors( 64, 100 ). Activation of luminal P2 receptors inrespiratory epithelium has two distinct effects on ion transport: 1 ) it activates NaCl secretion ( 46, 53, 100 )and 2 ) it inhibits electrogenic Na absorption( 18, 53, 93 ). Figure 1 showsa simplified schematic cell model of a secretory respiratory epithelialcell. Nucleotide-mediated activation of secretion in the airways waslater also shown to encompass activation of K secretion( 10 ). Rapidly, a number of essential steps forward weremade, driven by the putative therapeutic role of inhaled luminalnucleotides in the treatment of cystic fibrosis (CF). Luminal P2receptor stimulation activates mucociliary clearance in three ways: bytheir effects on ion transport, resulting in an increased hydration ofthe respiratory surface; by stimulation of mucin secretion from gobletcells ( 85 ); and by an increase in ciliary beat frequency( 67 ). A knockout study confirmed previous pharmacologicaldata and identified the P2Y 2 receptor subtype as thecrucial luminal P2 receptor in respiratory epithelium( 15 ). In addition to this, but of minor importance, aluminal P2Y 6 receptor is expressed in the luminal membraneof respiratory epithelia ( 75 ). Activation of luminalP2Y 2 (or P2Y 6 ) receptors increases intracellular Ca 2  concentration([Ca 2  ] i ), and subsequentlyCa 2  -activated Cl channels are stimulated,resulting in Cl secretion. Because in CF this"alternative Cl channel" is not defective, it mayserve to bypass the secretory defect when epithelium is stimulated withluminal nucleotides. The important question of the source of ATP in theluminal epithelial fluid continues to be poorly understood and will bediscussed below. Constitutive basal release of ATP has been describedas possibly generating sufficient concentration to stimulate luminal P2receptors ( 73 ). Physical stimuli are potent stimulators of luminal ATP release in respiratory epithelia, and this release occurswithout an effect on cell viability. Thus a mechanosensitive mechanismfor ATP release could be important and may be a component of the"cough reflex" ( 72 ). The irritant and the cough could stimulate ATP release into the luminal surface liquid, and subsequently the machinery of mucociliary clearance would be activated.+ o' p; u0 D$ Y4 X3 L" L
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Fig. 1. Schematic model of luminal P2Y 2 receptor-mediated ion transport regulation in respiratory epithelialcells. Cl secretion requiresNa -K -Cl cotransporter isoform 1 (NKCC1)-mediated, secondarily active Cl uptake on thebasolateral side and extrusion of Cl via either luminalCFTR or Ca 2  -activated Cl channels. LuminalATP/UTP stimulates Ca 2  -activated Cl channelsand thus Cl secretion. Electrogenic Na absorption occurs via luminal epithelial Na channels(ENaCs). Luminal ATP/UTP inhibits Na absorption. This alsoinvolves an increase in intracellular Ca 2  concentration([Ca 2  ] i ).
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LUMINAL P2 RECEPTORS IN GASTROINTESTINAL TRACT EPITHELIA* T$ Y) d5 t6 }( P' [5 N- K
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In addition to the lung and the epididymis, the activation of ionsecretion is also a hallmark of luminal P2 receptor stimulation in thegastrointestinal (GI) tract. In the GI tract, this comprises theactivation of K secretion in the distal colon( 58 ) and gallbladder ( 13 ); HCO 3 − secretion in the gallbladder ( 11 ), intrahepatic bile duct ( 22 ), and pancreatic duct( 54 ); and Cl secretion in biliary duct cells( 118, 129 ), gallbladder ( 13, 152 ), smallintestine ( 15 ), and cultured pancreatic duct cells ( 8, 105 ).( t( M' G( q( E" |' Z, h
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Luminal Nucleotides in GI Tract Glandular Secretion
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For salivary ( 78 ), bile ( 22, 118 ), andpancreatic ( 54 ) juice formation, the following has beensuggested and extends the two-step model (acinar production and ductalmodification) of glandular secretion by a luminal P2 receptorcomponent. In an initial step, ATP could be secreted by the acinarcells [salivary gland acini, hepatocytes, or pancreatic acini( 54, 79, 91 )]. Second, ATP, as it travels along the duct,would find luminal P2 receptors and influence ion transport to modifythe specific composition of the digestive juices. In support of thisconcept, recent results provide evidence for carbachol-stimulated ATPrelease from rat pancreatic acini ( 138 ). Thus aphysiological stimulus for the formation of primary pancreatic juicetriggers ATP release for further intraductal pancreatic juicemodification. A stimulating effect of luminal ATP/UTP onHCO 3 − secretion was recently shown in isolated guineapig pancreatic ducts ( 54 ). Interestingly, addition ofbasolateral ATP/UTP inhibited HCO 3 − secretion in thistissue. The luminal P2 receptor in guinea pig pancreatic duct appearsto be the P2Y 2 subtype ( 54 ). In rat pancreaticduct, evidence for a P2X 7 and P2Y 4 receptorwere recently presented ( 43, 91 ). It was also proposedthat duct cells themselves participate in luminal ATP release and thuswould regulate secretion in an autocrine or paracrine fashion( 54, 118 ).5 T, W5 G# x/ c7 P% r$ n! D: |
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In addition, the stimulation of Na /H exchanger type 3-mediated Na absorption via aP2X 7 receptor was proposed in rat submandibular gland ducts( 78 ). This presently appears to be the only result indicating that luminal P2 receptors activate absorption.

Luminal P2 Receptors in Large and Small Intestine7 g; [; C8 w0 J& [$ q
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It is noteworthy that similarly to airway epithelium, luminalP2Y 2 /P2Y 4 receptor stimulation alsoinhibits electrogenic Na absorption in the mouse distalcolon ( 81 ). The distal mammalian colon is analdosterone-sensitive epithelium that will absorb Na viaepithelial Na channels (ENaCs) in salt-restricted states( 70 ). In distal colon from normal and CF animals, luminalATP/UTP does not activate the alternative Cl secretorypathway discussed above, because CFTR appears to be the only apicalCl channel in this tissue ( 35 ). Nonetheless,the stimulation of luminal P2Y receptors in the colon (activation ofK secretion and inhibition of Na absorption)and small intestine (activation of Cl secretion) willresult in luminal fluid accumulation. As suggested for the airwayepithelium, luminal P2 receptors may thus serve a purpose in hostdefense reactions. Intraluminal intestinal bacterial overgrowth couldbe one source of luminal ATP/UTP, which would result in an associateddiarrhea response.2 C% Y1 b; r- p
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A recent immunocytochemical localization of luminal P2X 7 receptors in duodenal villus tip cells suggests yet another functional role of luminal P2 receptors. P2X 7 receptors have beenassociated with apoptosis in a large variety of cells( 113, 131 ). Epithelia in the urinary bladder or intestinalmucosa are rapidly regenerating mammalian tissues. In the intestinalmucosa, stem cells are located in the crypt base and, after havingmoved toward the surface, undergo programmed cell death and getexfoliated into the intestinal lumen. "Dying" cells eventually willrelease ATP and may therefore provide an extracellular death signal.P2X 7 receptors thus appear strategically located to ensuresmall intestinal epithelial regeneration ( 37 ).! H5 @) ~9 m* z6 o) V- B, g9 h+ w9 c
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OTHER EPITHELIA EXPRESSING LUMINAL P2 RECEPTORS8 g4 N# F/ E( K) m
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The ubiquitous nature of luminal P2 receptor expression in nearlyall epithelia is apparent from the long list shown in Table. 1. Anotherorgan with prominent luminal P2 receptor expression is the scala mediain the inner ear. The entire epithelial lining of the scala media inthe inner ear [vestibular dark cells and strial marginal cells of thestria vascularis organ ( 97, 98, 123 ), the Reissnermembrane epithelium ( 60 ), the Henson cells ( 71 ), and the sensory outer hair cells ( 48 )]shows expression of different luminal P2 receptors. For a comprehensivedescription, the interested reader is referred to a recent review byHousley ( 48 ). Other epithelia with luminal P2 receptorsnot mentioned before include sweat gland acinar cells( 156 ) and the conjunctival epithelium of the eye( 87 ). In both tissues, stimulation of these receptorsinduce Cl secretion. An understanding of the role of P2receptors in these and other tissues awaits further studies.

LUMINAL P2 RECEPTORS ALONG THE NEPHRON4 D$ G( w. A0 X( {: }1 \8 y
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An increasing number of studies have focused on P2 receptors inrenal epithelia, an issue recently reviewed comprehensively ( 134 ). The fact that renal epithelial cells may alsoexpress luminal P2 receptors has been suggested by a number of studies using cultured cells of distal tubular origin ( 16, 34, 102, 135 ). In cultured renal epithelial cells, the functionalresponses resemble those of the respiratory or other secretoryepithelia. Luminal nucleotides increase[Ca 2  ] i, activate Cl secretion,and inhibit Na and Ca 2  absorption ( 16, 34, 68, 102, 135 ). Most recently, the luminal expression of aP2Y 2 receptor in the intact isolated perfused corticalcollecting duct of the mouse was demonstrated ( 17, 80 ).Pharmacological screening suggested that this receptor is the onlyluminal P2 receptor subtype expressed in the distal nephron.High-resolution confocal imaging unequivocally demonstrated that theP2Y 2 receptor was located in principal cells. It ispresently uncertain whether rat intercalated cells also express luminal P2 receptors. For rabbit cortical collecting duct, the functional expression of luminal P2Y 2 /P2Y 4 on intercalatedcells has recently been reported ( 158 ). The expression ofluminal P2Y 2 receptors appears to occur along the entiredistal nephron, down to the inner medullary collecting duct ( 17, 62, 68, 83 ). Apparently, mice, rats, and rabbits show thisluminal receptor expression. In the intact collecting duct, luminalATP/UTP inhibited electrogenic Na transport. Atransepithelial electrical signal indicative of Ca 2  -activated Cl secretion, however, was notobserved in the native epithelium ( 80, 128 ). It istherefore assumed that Ca 2  -actived Cl channels are not expressed in native cortical collecting duct principalcells. This situation is reminiscent of a number of studies in colonicepithelia, where CFTR is the only luminal Cl channelmediating Cl secretion ( 35 ). However, thisis not the case in cultured colonic epithelia like T84 or HT29 cells,where in addition to CFTR a Ca 2  -activated Cl conductance also mediates Cl secretion ( 2, 19, 36 ). It is therefore speculated that cultured distal tubularepithelia exhibit a less differentiated state and displayCl secretory properties normally not seen in thewell-differentiated tissue. In addition, P2Y 2 receptorstimulation in mouse cortical collecting duct principal cells alsoinhibited apical ROMK channels and thus K secretion( 89 ). These experiments were performed in split-open tubules and are thus likely to involve luminal P2 receptor stimulation. Presently, it is not known whether transport of urea andH 2 O is also influenced by luminal ATP/UTP. Noteworthy hereare two studies that demonstrated that basolateral P2 receptorstimulation inhibited aquaporin-2 (AQP2)-mediated H 2 Otransport ( 61, 121 ). Thus it may be concluded that luminalP2Y 2 receptor stimulation inhibits at least three, if notall, relevant transcellular transport processes for salt and waterabsorption in collecting duct principal cells. Figure 2 schematically summarizes the effect ofluminal ATP/UTP as an inhibitory transport regulator in distal tubularprincipal cells. Given that nearly all epithelia express luminal P2receptors, it appears likely that other more proximal parts of thenephron also express luminal P2 receptors. In our own preliminaryexperiments using perfused mouse cortical thick ascending limb ofHenle's loop, however, we could not find a luminal ATP-induced[Ca 2  ] i increase. However, this may not fullyexclude the presence of luminal P2 receptors in cortical thickascending limb of Henle's loop, and further studies are required.Noteworthy is a recent study in which the so-calledP2X cilia (possibly P2X 4 ) receptor was shown tobe only capable of activation if extracellular Na was low( 92 ).. I! W0 ^$ f8 |2 v+ @& v

Fig. 2. Schematic model of luminal P2Y 2 receptor-mediated inhibition of transport in distal tubular principalcell. Luminal ATP/UTP inhibits Na and Ca 2  absorption and K secretion. Transduction events involvedare not clarified but do not appear to involve[Ca 2  ] i. ECaC, epithelial Ca 2  channel; AQP2, aquaporin-2.

Luminal ATP and Flow-Dependent Regulation of Tubular Transport?, a6 c: |8 u+ w: W

An increase in tubular flow in the nephron is known to increaseK secretion ( 33, 59, 94 ) and Na absorption ( 127 ). This effect is thought to reflect inpart the increased delivery of Na to more distal nephronsegments and subsequent apical membrane depolarization with theresulting increase in driving force for K exit via luminalROMK channels ( 31 ). In addition, activation ofmaxi-K channels mediated by increased tubular flow wasrecently shown ( 144, 157 ). Regarding Na absorption, evidence suggests that an increase in flow could lead todirect "mechanical" activation of ENaC channels ( 127 ). In addition, one may suggest that luminal ATP contributes toflow-dependent K and Na transport. Eventhough the mechanism of ATP release continues to be obscure, we havelearned that different nonexcitable cells display constitutive ATPrelease ( 73, 145 ). Assuming that this is also truefor the nephron, one could envisage that an increase in flow could washout luminal ATP and thus relieve a proposed tonic inhibition of luminalROMK and ENaC channels. In conflict with this is the flow-dependentincrease in K secretion via maxi-K channels( 157 ). The authors also showed that elevation of flow increased [Ca 2  ] i ( 157 ). It hasbeen shown for endothelial cells that an increase in flow can result inan increase in ATP release ( 74 ). It may thus bespeculated that tubular flow increase triggers luminal ATP release andsubsequent activation of maxi-K channels. This issue hasrecently been addressed from yet another angle. The functionalsignificance of the rather obscure central luminal cilium wasinvestigated in Madin-Darby canine kidney cells, and a mechanosensoryrole was proposed ( 112 ). Increasing superfusion flow orbending the central cilium directly triggered[Ca 2  ] i elevations and hyperpolarized thecell. Indirect arguments are presented that ATP release is not involvedin this effect. Thus the activation of maxi-K channels mayinvolve a mechanosensory event independently of ATP release. Insummary, K secretion induced by increased flow could becomposed of independent but concerted events: 1 ) increaseddelivery of Na to more distal nephron segments; and 2 ) mechanosensitive activation of maxi-K channels. In addition, washout of luminal ATP could contribute to this effect.

PREVALENCE OF LUMINAL P2Y 2 RECEPTORS, V; o# J9 ?& m3 }! @7 Y
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It is a prominent finding that nearly all native tissues describedabove respond equally well to ATP and UTP. Inspection of the extensivelist of epithelial tissues shown in Table 1 indicates that theP2Y 2 receptor is a very prevalent luminal P2 receptor intransporting epithelia. Importantly, however, one needs to considerthat the similar "agonist profile" of the P2Y 2 andP2Y 4 receptors makes a functional discrimination betweenthem difficult ( 113 ). A recent P2Y 2 receptorknockout study has clarified some issues in this context. Whereas inrespiratory epithelium the P2Y 2 receptor indeed appears tobe the critical player in luminal nucleotide-stimulated effects, it isapparently of no importance for the small intestinal effects( 15 ). Also, in the stria vascularis of the inner ear itwas previously thought that a luminal P2U receptor mediated inhibitionof K secretion ( 98 ) with novel evidenceshowing a luminal P2Y 4 receptor in this tissue ( 97, 123 ). An inspection of Table 1 also clearly shows that theexistence of numerous other luminal P2 receptors (P2Y 1,P2Y 4, P2Y 6, P2X 2, P2X 4,P2X 5, P2X 7 ) has been suggested. It is thereforeapparent that epithelial cells commonly (if not always) expressmultiple P2 receptors (P2X and P2Y) and these may be present in thesame membrane domain ( 9, 22, 43, 51, 58, 82, 91, 101, 134, 146 ). In renal epithelium, so far the only luminal P2 receptorwas the P2Y 2 subtype (see Table 1 ). However, not allepithelia express luminal P2Y 2 receptors. Two examples hereare Calu-3 cells (secretory cell line derived from submucosal bronchialglands) ( 49 ) and rat submandibular gland duct cells( 79 ).

SOURCE AND FATE OF LUMINAL NUCLEOTIDES  o; ^; s& `; W5 V7 V
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The luminal expression of P2 receptors has triggered the importantquestion of the source of luminal nucleotides. In the absence of anyother specific source (e.g., nerve endings), a larger number ofstudies have led to the accepted proposal that the epithelial cellitself is a source of the released nucleotide. ATP release has beenshown for a variety of epithelia and other cells, and in epitheliarelease appears to occur preferentially onto the luminal side. A numberof reviews have recently summarized the present state of knowledge( 41, 118, 145 ). Any mechanical perturbation [touching thecell with a glass pipette ( 12, 24 ), increasing superfusionflow ( 74, 99, 124 ), cell swelling with hyposmolarsolutions ( 145, 153 ), or just mechanical shaking of aculture dish ( 38, 42, 76 )] has been shown to induce ATPor UTP release without apparent cellular damage. The release pathwayfrom epithelial cells has been assumed to be either by a conductivepore ( 23 ), a specialized membrane transporter, orvesicular release and exocytosis ( 118 ). CFTR anionchannels and ABC transporters like MDR1 were suggested toconduct/transport ATP ( 118, 133 ), but subsequent studiescould not confirm that CFTR functions directly as an ATP-conductivepore ( 38, 86, 115, 154 ). Importantly, in CF epithelia ATPrelease is absent ( 116 ), and CFTR has been suggested toregulate an associated ATP channel in epithelia ( 57, 142 ).A recent study using mutational alterations to change the substratespecificity of the MDR1 transporter reported no effect on ATP release( 119 ). Thus the authors argue that MDR1 is not likely tofunction as an ATP transporter. However, upregulation of MDR1 augmentedATP release in hepatoma cells, implying a possible indirect mechanismof MDR1 on ATP release ( 119 ). Whether ATP release canoccur via vesicular fusion and exocytosis will need further studies,but evidence supporting this concept has been presented ( 99, 103, 116, 138 ).0 P) f" R( z# Y# {1 A
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Even though ATP release has been demonstrated to occur preferentiallyonto the luminal side of epithelial cells, basolateral ATP release hasalso been shown. This basolateral ATP release has been suggested tooccur after "luminal damage" (e.g., a kidney stone in the ureter)and may convey information to the central nervous system viaP2X 2 /P2X 3 receptors located on sensory nerves. Thus a basolateral release has been suggested to play a role in mechanosensory transduction ( 7 ).

The propagation of [Ca 2  ] i increases fromcell to cell is a widely distributed phenomenon attributed to thespread of inositol 1,4,5-trisphosphate through gap junctions ( 30, 39 ). In addition, in epithelial and nonepithelial cells releasedATP has been discovered to act as an extracellular signal responsiblefor "traveling [Ca 2  ] i waves" ( 12, 24, 130 ). ATP release is triggered from a site of initiation(e.g., by touching a cell with a pipette) and diffuses to neighboringcells. This, in turn, stimulates P2 receptors, which induceintracellular [Ca 2  ] i signals and again ATPrelease, resulting in a traveling [Ca 2  ] i orextracellular ATP wave. In poorly gap junctional-coupled cell lines,the expression of different connexons (Cx43, Cx32, Cx26) was recentlyshown to greatly augment ATP release ( 12 ). At the sametime, it was also noticed that connexons (hemichannels) can befunctional channels and allow the permeation of Lucifer yellow whenlowering extracellular Ca 2  ( 44 ). A recentstudy in astrocytes presented evidence that ATP is directly conductedthrough connexon hemichannels. Dye flux was molecular weight specific,induced by mechanical stimulation, and blocked by Gd 3  andflufenamic acid ( 140 ). Certainly, these results demandfurther rigorous experimental proof, but on the basis of these novelresults, one might speculate that connexon hemichannels could belocalized in the apical membrane of epithelia and thus provide an exitpathway for secreted ATP. This hypothesis, however, includes acontradiction because [Ca 2  ] i waves mediatedby ATP release were described to be uninfluenced by gap junctionalblockers ( 12 )./ D* J: ^" e% u" M( |. }' B$ t

Fate
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After their release, nucleotides will be metabolized. Thisis executed by membrane surface-located ecto-nucleotidases. The fieldof extracellular surface enzymes involved in metabolizing extracellularnucleotides is presently expanding rapidly ( 163 ). Ecto-nucleotidases encompass several families with partiallyoverlapping substrate specificities. The most prominent familyencompasses the ecto-nucleotidase triphosphate diphosphohydrolases(NTPDases, etc. syn: CD39 or apyrase), which hydrolyze ATP andADP to generate AMP ( 162 ). Subsequently,ecto-5'-nucleotidase will generate the nucleoside and phosphate( 77, 163 ). Other ectonucleotidases encompass the alkalinephosphatase and the ecto-phosphodiesterase/pyrophosphatase family. Acomprehensive review of this issue is not intended here, and the readeris directed to pertinent reviews in the field ( 42, 73, 77, 162-164 ). However, it should be mentioned that themetabolism of extracellular nucleotides is more complicated thaninitially assumed. Nucleotides cannot only be degraded but alsoupgraded (by "ecto-kinases"). The identification of extracellularnucleoside diphosphokinase has revealed this phenomenon. In thepresence of ATP and UDP, for example, this enzyme can mediate theformation of ADP and UTP ( 73 ). In addition, matters arefurther complicated by the recognition that not only nucleotides butalso their metabolizing enzymes (NTPDase, nucleosidediphosphokinase) can be secreted into the extracellular space assoluble proteins ( 21, 163 ). In the context of this review,it is important to note that luminal ecto-nucleotidases have beenidentified and localized, for example, in respiratory epithelium( 21 ) and rat pancreatic duct ( 106 ). In thekidney, early data from 1972 indicated that isolated tubule segmentswere able to hydrolyze added ATP ( 120 ). Later proximal tubule brush-border membrane and basolateral membrane vesicles weredescribed to exibit ecto-ATPase activity ( 122 ). CD39 was recently shown in the renal vasculature but not in medullary nephron segments ( 84 ). More comprehensive data areavailable for the localization of ecto-5'-nucleotidase in the nephron.It is noteworthy that ecto-5'-nucleotidase belongs to thephosphatidylinositol-anchored proteins, which are localizedspecifically in the luminal membrane of epithelia ( 77 ). Itis thus expressed in the luminal membrane of proximal tubules anddistal tubular intercalated cells but apparently not in the thickascending limb of Henle ( 77 ). Thus the luminal side ofepithelia including the nephron contains important establishedcomponents of the "ATP-signaling machinery," i.e., P2 receptors,released agonists, and metabolizing enzymes.
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RELEASED LUMINAL ATP AS PRECURSOR FOR ADENOSINE-REGULATED IONTRANSPORT6 V' O3 G- K9 ^( d$ w  q: K
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The preceding comments imply that epithelial transport is not onlyregulated by the different nucleotides but also by adenosine as adegradation product of ATP ( 29 ). Evidence for this has been presented, for example, in T84 enterocytes, where luminal ATPexerts a Cl secretory effect via A 2 adenosinereceptors and is associated with an increase in cAMP( 141 ). Evidence for ecto-ATPase activity on the luminalside of the small intestine has been presented ( 132 ), andmost likely a luminal ecto-5'-nucleotidase is also present on theluminal side of intestinal epithelia ( 141 ). A similarphenomenon was observed in Calu-3 cells, a cell line derived fromsubmucosal respiratory glands. Calu-3 cells do not express luminalP2Y 2 receptors but release ATP after mechanicalstimulation. Adenosine is subsequently generated, stimulatesA 2b adenosine receptors, and then a cAMP-mediatedCl secetion occurs via CFTR. The authors also present theinteresting finding that cAMP-mediated signaling in response toA 2b receptor activation is localized to the subapicalmembrane of these airway epithelial cells ( 49 ). In thekidney, the urinary excretion of adenosine is well documented andincreases strongly during renal ischemia ( 3, 108 ).In the mammalian nephron, no evidence to date suggests that luminaladenosine modulates epithelial transport ( 77 ). In the Xenopus laevis renal epithelial A6 cell line, however, luminal A 1 adenosine receptors have been identified( 1, 20 ), and it may well be that luminal adenosinereceptors will be discovered in the intact mammalian nephron in thenear future.

FUNCTIONAL IMPLICATIONS FOR LUMINAL P2 RECEPTORS IN EPITHELIA
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Given their ubiquitous expression, one is tempted to search for acommon functional purpose of luminal P2 receptors in epithelia. Presentknowledge makes this task difficult, and different organ systems arelikely to have developed luminal P2 receptors for specific purposes.The formulation of one common function is certainly hampered by thelack of essential pieces in this puzzle. Receptor identification islikely to be incomplete, the molecular release mechanism and itsprecise regulation are obscure, and the fate of released ATP processedby the increasingly growing family of nucleotide-metabolizing enzymesawaits further specification. Nonetheless, the above-mentioned findingsmake it possible to extract common denominators for functionalintegrative schemes. Some suggestions for an integratedfunctional role of luminal P2 receptors are elaborated below. Emphasiswill be given to renal tissue.1 `5 L8 X( \) i

Luminal P2 Receptors Involved in a Nonspecific Epithelial DefenseMechanism

This concept was originally postulated for the respiratoryepithelium ( 72 ) but may extend to other epithelialtissues. In the respiratory tract, the outer eye, and the intestinaltract, luminal nucleotides stimulate ion secretion. These epithelia are vulnerable body surfaces, where exogenous harmful particles or bacteriacan produce extensive local damage. Each of these epithelial organs hasspecific armaments to counteract potential threats on their luminalsurface. It is proposed that the epithelial defense mechanisms alsoinvolve luminal P2 receptors. A noxious particle would mechanicallytrigger nucleotide release. Luminal ATP could also originate from abacterial source or from dying defense cells, which have migrated intothe epithelial lumen. Subsequently, P2Y 2 receptor-mediatedsecretion/inhibition of absorption would be stimulated. Thus largeramounts of luminal fluid would be generated and therefore would help toflush away the luminal irritant. For example, large amounts of purulentsputum in bacterial bronchitis may well be explained by the stimulationand activation of mucociliary clearance via luminal P2Y 2 receptors.
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P2 Receptors and the Regulation of Cell Volume

Cell volume regulation is an important property of all cells. Itis likely to be of extraordinary importance in epithelial cells, whererapid changes in transcellular flux of fluid and solutes occur. It iseasy to conceive that any imbalance of luminal uptake and basolateralextrusion will compromise cell volume. This is beautifully exemplifiedin macula densa cells. Reduction of apical ion influx via theNa -K -Cl cotransporter isoform 2 (NKCC2) reduces cell volume and vice versa ( 32 ). A rolefor extracellular ATP and P2 receptors has recently been demonstratedin rat hepatoma ( 153 ) and bile duct epithelia( 118 ). In both cell types, cell swelling was shown torelease ATP, activate P2 receptors and, subsequently,Ca 2  -activated K and Cl conductances. The resulting cellular KCl loss mediates regulatory volume decrease ( 45 ). In an extrapolation from theseresults, luminal P2 receptors may serve to regulate cellular volume in transporting epithelia. P2 receptor-mediated activation ofK and Cl channels is also seen in culturedrenal epithelia ( 1, 5, 16 ). However, to date there is noevidence for Ca 2  -activated Cl channels inintact nephron segments, and it is uncertain whether the mechanismdescribed applies to renal tubules. However, another mechanism toregulate cellular volume via luminal P2 receptors can be postulated. Acommon functional consequence of extracellular ATP action in the distaltubule is the inhibition of the major transport processes. Thusincreases in transcellular transport would increase cell volume, elicitregulated ATP release, and so induce autocrine activation of luminal(and basolateral) P2 receptors. This would downregulate apicalsubstrate influx and thus provide a negative-feedback regulation ofcellular volume. This hypothesis requires rigorous testing. Onebeautiful example that illustrates the issue of volume regulation, ATPrelease, and regulated cell function deserves mentioning here. UsingA 1 receptor knockout mice, it has recently been shown thatadenosine is the extracellular mediator of tubuloglomerular feedback(TGF) ( 6, 143 ). In TGF, the macula densa senses the distaltubular sodium load via the NKCC2 cotransporter. This probably occurs via a change in cellular volume because macula densa cells strongly change their volume in response to luminal electrolyte uptake ( 32 ). Cell volume increases induced by increasing luminalNaCl concentration have recently been shown to stimulate ATP release into the basolateral interstitial space ( 4 ). Released ATPis suggested to be broken down, and the adenosine formed by the5'-nucleotidase will subsequently constrict preglomerular arterioles( 148 ). This feedback is disrupted by knockout ofA 1 receptors. These results highlight the importance ofcell swelling-induced release of ATP in TGF regulation.

ATP and Ischemic Protection in the Kidney  \/ v# ^9 d* r

In the intact distal nephron, a consistent finding has been thatall major transporting activity is downregulated when luminal and/orbasolateral P2Y receptors are activated ( 61, 68, 80, 89 ).For more proximal tubular segments, this has not been studied in anydetail, and it might be a peculiar property of the distal nephron. Inthe distal tubule, at least, it is proposed that extracellular (luminal) ATP acts as a luminal signaling molecule and serves toprotect the tubular epithelium under ischemic conditions (Fig. 3 ). The sequence of events could be asfollows. In ischemia, epithelial cells will suffer energydepletion and therefore swell. ATP is subsequently released fromepithelial cells by cell swelling ( 69, 73, 145 ). This, inturn, will trigger regulated ATP release and autocrine or paracrine P2receptor stimulation. The released ATP could enter the tubular fluidand move along the nephron to autoinhibit energy-consuming transportprocesses in more distal tubular segments and so protect them.Basolateral P2 receptors could mediate a similar process. Obviously,nucleotides could also originate from the vascular space and enter thenephron via glomerular filtration.
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Fig. 3. Schematic model of "ischemic protectionhypothesis." Proximal endotubular ATP is proposed to lead to distaltubular transport inhibition and thus epithelial protection.
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In renal ischemia, increased amounts of adenosine are releasedinto the urine ( 108 ), but it is likely that ATP is theprimary metabolite released from ischemic cells and that it isthen converted to adenosine (see above). In addition, extracellular ATPacting via P2 receptors has been shown to stimulate cell growth anddivision in a number of renal ( 40, 50, 55, 109 ) andnonrenal tissues ( 47 ). An intriguing preliminary studysuggests that shortly after renal ischemia, ion transportprocesses are downregulated, whereas expression of the P2Y 2 receptor itself is upregulated ( 63 ). It is thereforesuggested that ATP acts as an "intelligent" extracellular signalingmolecule that can prevent ischemic damage almost before itoccurs but which can also assist in cell recovery and regenerationafter damage has happened.
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It has been indicated above that the focus on P2 receptors and ATPimplies a rather crude simplification of matters, because released ATPwill provide the source for the formation of adenosine with numerouseffects mediated via adenosine receptors. Recently, A 2a adenosine receptors were shown to play an important role as aphysiological feedback mechanism for the limitation and termination ofboth tissue-specific and systemic inflammatory responses ( 29, 107 ). This is worth mentioning in this context because P1 and P2receptors may serve a common purpose in a concerted effort to limittissue damage by noxious events of different origin.5 U5 w- Z7 G: r& u# v4 f5 p" f
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Luminal P2 Receptors in Polycystic Kidney Disease
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Luminal P2 receptors have been suggested to play an important rolein the course of polycystic kidney disease (PKD) ( 135, 155 ). PKD is associated with the formation of cysts derived from renal tubular epithelia. It is the expansion of cysts that determines the progression of disease and development of renal failure. Expansion of cysts is driven by two processes, cellular proliferation and fluidsecretion, leading to progressive cyst enlargement. Although cysts canarise from any portion of the renal tubule, evidence from models ofautosomal dominant PKD in both mice ( 90 ) and rats( 14 ) suggests that cysts originate mainly from proximal tubular cells; the same also seems to be true in the recessive form of this disease ( 96 ). It has been suggested that avariety of different locally released factors acting as autocrine orparacrine regulators stimulate renal cyst growth and expansion( 117 ). Intriguingly, primary cultured PKD cyst epithelialcells were recently shown to express luminal P2Y and P2X receptors andsecrete ATP onto the luminal side (i.e., into the cyst lumen)( 135 ). In PKD, epithelial luminal ATP was also shown tostimulate Cl secretion ( 135 ). Furthermore,it was shown that cyst fluid contains significant concentrations of ATP( 155 ). Thus ATP could be one of the local factors involvedin progression of PKD cysts.5 \. [" ?3 P3 i+ Y9 _- \$ f

ACKNOWLEDGEMENTS
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I appreciate comments on improving this manuscript from Dr. IvanaNovak, August-Krogh-Institute, Copenhagen, Denmark.0 i2 Y1 |8 {0 S* v/ ^
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