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Acid-Base Transport Systems in Gastrointestinal Epithelia

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Acid-Base Transport Systems in Gastrointestinal Epithelia 134 Gut 1992;33: 1134-1145 PROGRESS REPORT Gut: first published as 10.1136/gut.33.8.1134 on 1 August 1992. Downloaded from Acid-base transport systems in gastrointestinal epithelia D Gleeson Cell plasma membranes contain a variety of transport systems that carry acid or base into or out ofthe cell. Research over the past decade has led to remarkable advances in our understanding of these acid-base transport systems and has established that they have several major physio- logical roles. They are the primary means by which cells regulate their internal pH and they also contribute importantly to regulation of cell volume and possibly cell proliferation. Further- more, in the gastrointestinal tract they mediate absorption and secretion, not only of acids and bases but of several other electrolytes and nutrients. The major acid-base transport systems on mammalian cell plasma membranes are illustrated in Figures 1-3; their specific locations on different cell types are discussed later. Hydrogen, potassium (H+,K+) adenosine tri- phosphatase (ATPase) extrude H+ in exchange http://gut.bmj.com/ for K' using energy derived directly from ATP hydrolysis. They are present on the apical mem- branes of gastric parietal cells' (Fig 1) and, in some species, colon epithelial cells,2 where they mediate acid secretion. However, they are not widely distributed in gastrointestinal epithelia. Other acid base transport systems derive their H+ HCO3- 3Na+ on September 24, 2021 by guest. Protected copyright. not from ATP but energy, directly hydrolysis, Figure 1: Acid-base transport systems on an activated gastric from coupling the movement of one ion to parietal cell. The apical membrane contains H+-K+ A TPase passive movement of another ion along its and the basolateral membrane contains Na+lH+ exchange, electrochemical gradient. In the case of sodium/ Cl-IHCO3 exchange, and Na+-HCO3 co-transport. The stochiometry ofthe Na+-HCO3 co-transporter is not known hydrogen (Na+/H+) exchange (Figs 1-3), H' (n= 1, 2, or 3). Note also basolateral membrane Na+-K' extrusion from the cell is coupled, in a 1: 1 ratio, A TPase and apical membrane Cl- and K+ channels. For to Na+ entry down its chemical gradient.3-' This details, see text (section 2). As in Figures 2 and 3, the transport systems which derive their energy directlyfrom A TP gradient depends on the sodium pump, Na+,K+ hydrolysis, are shown in closed circles. ATPase, which is present on the basolateral membrane of all gastrointestinal epithelial cells and extrudes 3 Na+ ions in exchange for 2 K+ is a result of the negative intracellular potential, ions, thus maintaining a low intracellular [Na+], which maintains a low intracellular [Cl -]. In the high intracellular [K'], and negative intra- case of Na+-HCO3 co-transport (Figs 1, 3), cellular potential. Na+/H+ exchange is almost HCO3- movement is coupled with that ofNa+ in ubiquitous in mammalian cells and can be the same direction. In most, although not all, inhibited by the diuretic amiloride. cells this sytem operates in the direction of Na+ There are several mechanisms for bicarbonate and HCO3- entry into the cell, the driving force, (HCO3 ) transport across plasma membranes.67 as for Na+/H+ exchange, being the out to in Na+ In most tissues, the enzyme carbonic anhydrase gradient. Typically, Cl-/HCO3- exchange and Gastroenterology Unit, of H' and are not affected Royal Hallamshire mediates rapid equilibration HCO3 Na+-HCO3- co-transport by Hospital, Sheffield with C02, which diffuses freely across all cell amiloride but can be inhibited by the disulphonic D Gleeson membranes. Therefore, HCO3 transport into stilbene DIDS.67 Finally, HCO3- can exit from Correspondence to: the cell is equivalent to H` transport out of the some cells' uncoupled to other ions, via plasma Dr D Gleeson, Gastroenterology Unit, Floor cell and vice versa. membrane HCO3- channels (Fig 3). The driving J, Royal Hallamshire Hospital, In the case of chloride/bicarbonate (Cl-/ force here is the negative intracellular potential. Glossop Road, Sheffield S10 2JF HC03 ) exchange (Figs 1-3), HCO3 extrusion There have been two major approaches to Accepted for publication from the cell is coupled, in a 1:1 ratio, to Cl characterising acid-base transport systems. 4 November 1991 entry along its chemical gradient. This gradirnt Firstly, by studying radiolabelled ion uptake Acid-base transport systems in gastrointestinal epithelia 1135 H+ HCO3-- transmitters, and growth factors, acting via intracellular mediators. On the other hand, 4~ measurement of pHi using fluorescent dyes has usually necessitated cell dispersal, following Gut: first published as 10.1136/gut.33.8.1134 on 1 August 1992. Downloaded from which epithelial cells often lose their polarised characteristics. Consequently, selective assay of Na+ Ci- apical and basolateral transport systems has usually not been possible. Studies of isolated vesicles and studies of cell pHi, although providing complementary data on acid base transport systems, have defined them in purely functional terms. However, applica- tion of molecular biological techniques has recently yielded information regarding the molecular structure of these transport systems. For example, Sardet et al have obtained a human cDNA sequence from human fibroblasts, expression of which restores Na+/H+ exchange activity in a mutant fibroblast which lacks intrinsic Na+/H+ exchange.2627 The putative Na+ 2K+ Na+/H+ exchanger encoded by this cDNA sequence is a 815 amino acid glycoprotein with 10-12 hydrophobic (possibly membrane span- ning) domains at its amino terminal. The Cl-/ HCO3- exchanger in red blood cells has also K+ Cl- been cloned and sequenced.28 Very recently, H+ 3Na+ similar approaches have been used to isolate Figure 2: Acid-base transport systems on a NaCI absorbing cDNA sequences encoding Na+/H+ and Cl-/ cell. Examples include ileal villus, colon, and gall bladder HCO3 exchangers from rabbit ileum (see epithelial cells. The apical membrane contains coupled Na+l below). H' and Cl-/HCO3 exchangers. The basolateral membrane contains another Na+lH+ exchanger with different kinetic characteristics and, in addition, Na+-K' ATPase and K' and Cl- channels. In some cells'5 basolateral K' and Cl- exit is via a KCL co-transport system. For details see text (section 3). http://gut.bmj.com/ into isolated plasma membrane vesicles. For example, in many tissues, 22Na can be shown to be concentrated into plasma membrane vesicles in the presence of an in to out transmembrane H+ gradient. Furthermore, a major component ofthis Na+ uptake is a saturable function ofNa+ on September 24, 2021 by guest. Protected copyright. concentration, is temperature sensitive, is electroneutral (that is, unaffected by trans- membrane potential), and is inhibited by amiloride. These properties are characteristic of a Na+/H+ exchange mechanism. Isolated vesicles were used in the first direct demonstra- tion of Na+/H+ exchange, by Murer in rabbit jejunum.9 Similar studies have shown that not only Na+/H+ exchange,"-'7 but also, Cl-HCO3- exchange'8 23 and Na+-HCO3- co-transport2425 are widely distributed in gastro- intestinal epithelia from several species includ- ing humans. Furthermore, selective isolation of vesicles from basolateral and apical membranes has often revealed a polarised distribution of these transport systems between the two mem- branes (Figs 1-3). This polarisation, as discussed below, is fundamental to the role of acid-base transport systems in transepithelial transport. H+ 3Na+ Figure 3: Acid-base transport systems on a HCO3- secreting Acid-base transport systems can also be cell. Examples include ileal crypt cells, hepatocytes, and, characterised in intact cells by their effects on probably, duodenal epithelial cells and pancreatic and bile intracellular pH (pHi), an approach facilitated in ductular cells. The apical membrane contains Cl-IHCO3 exchange, Cl- channels, andpossibly (?), separate HCO3 recent years by the advent of pH sensitive channels andlor Na+-HCO3 co-transport. In order to fluorescent dyes. This approach offers the operate in the direction ofHCO3 extrusion, the apical important advantage that the normal environ- Na+-HCO3 co-transporter would have to transport a ment the and has negatively charged species, that is n=2 or 3. The basolateral of transporter is preserved membrane contdins Na+IH+ exchange and Na+/HCO3 co- provided evidence for regulation of acid-base transport (the stochiometry ofwhich is not known), together transport systems by many hormones, neuro- with Na+-K' ATPase. For details see text (section 4). 136 Gleeson Functional roles of acid base transport coupled to the Na+ gradient, which drives it systems 'uphill,' that is Cl- out of and HCO3- into the cell. Na+ dependent Cl-/HCO3- exchange is an (1) REGULATION OF INTRACELLULAR pH (pHi) important pHi regulatory mechanism in inverte- Gut: first published as 10.1136/gut.33.8.1134 on 1 August 1992. Downloaded from In most cells, pHi is actively maintained between brate cells and in mammalian mesenchymal 7.00 and 7.40, almost one unit above the value cells67 but has not yet been described in gastro- expected if intracellular and extracellular H+ intestinal epithelia. were in electrochemical equilibrium. Further- more, pHi can recover spontaneously to baseline within minutes after exposure of cells to acute (2) GASTRIC ACID SECRETION (FIG 1) acid and alkaline loads.67 Regulation of pHi is of Gastric acid secretion is mediated by a H+,K+ major importance to cell homeostasis because ATPase on the apical membrane of the parietal many physiological phenomena are pH depen- cell which extrudes H' in exchange for K+.4 dent29; diverse examples include the rate of The enzyme has recently been cloned and glycolysis,30 the level of intracellular calcium,3' sequenced.3' Its molecular weight is about 95 000 and plasma membrane K' permeability which Daltons and it consists of two subunits: a larger may regulate intracellular electrical potential.`23 alpha subunit with several membrane spanning In most cells, including several gastro- domains and a smaller beta subunit.
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