Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes
2000; Elsevier BV; Volume: 57; Issue: 2 Linguagem: Inglês
10.1046/j.1523-1755.2000.00857.x
ISSN1523-1755
AutoresManoocher Soleimani, Charles E. Burnham,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoPhysiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes. Approximately 80% of the filtered load of HCO3- is reabsorbed in the proximal tubule via a process of active acid secretion by the luminal membrane. The major mechanism for the transport of HCO3- across the basolateral membrane is via the electrogenic Na+:3HCO3- cotransporter (NBC). Recent molecular cloning experiments have identified the existence of three NBC isoforms (NBC-1, NBC-2, and NBC-3). 1At the time this paper was under review, the cloning of a new NBC isoform, which is also called NBC-3, was reported (Pushkin A, Abuladze N, Lee I, Newman D, Hwang J, Kurtz I. J Biol Chem 274:16569–16575, 1999). We therefore have two distinct NBC-3 isoforms. To prevent any confusion, they are named kNBC-3 (reference 85) and mNBC-3 (Pushkin et al, see above). mNBC-3 is expressed only in myocytes and myocardium. kNBC-3 (reference 85) is the isoform expressed in kidney and other tissues. The term "NBC-3" used in this article refers to kNBC-3.1At the time this paper was under review, the cloning of a new NBC isoform, which is also called NBC-3, was reported (Pushkin A, Abuladze N, Lee I, Newman D, Hwang J, Kurtz I. J Biol Chem 274:16569–16575, 1999). We therefore have two distinct NBC-3 isoforms. To prevent any confusion, they are named kNBC-3 (reference 85) and mNBC-3 (Pushkin et al, see above). mNBC-3 is expressed only in myocytes and myocardium. kNBC-3 (reference 85) is the isoform expressed in kidney and other tissues. The term "NBC-3" used in this article refers to kNBC-3. Functional and molecular studies indicate the presence of all three NBC isoforms in the kidney. All are presumed to mediate the cotransport of Na+ and HCO3- under normal conditions and may be functionally altered in certain pathophysiologic states. Specifically, NBC-1 may be up-regulated in metabolic acidosis and potassium depletion and in response to glucocorticoid excess and may be down-regulated in response to HCO3- loading or alkalosis. Recent studies provide molecular evidence indicating the expression of NBC-1 in pancreatic duct cells. NBC is activated by cystic fibrosis transmembrane conductance regulator (CFTR) and plays an important role in HCO3- secretion in the agonist-stimulated state in pancreatic duct cells. The purpose of this review is to summarize recent functional and molecular studies on the regulation of NBCs in physiologic and pathophysiologic states. Possible signals responsible for the regulation of NBCs in these conditions are examined. Furthermore, the possible role of this transporter in acid-base disorders (such as proximal renal tubular acidosis) is discussed. Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes. Approximately 80% of the filtered load of HCO3- is reabsorbed in the proximal tubule via a process of active acid secretion by the luminal membrane. The major mechanism for the transport of HCO3- across the basolateral membrane is via the electrogenic Na+:3HCO3- cotransporter (NBC). Recent molecular cloning experiments have identified the existence of three NBC isoforms (NBC-1, NBC-2, and NBC-3). 1At the time this paper was under review, the cloning of a new NBC isoform, which is also called NBC-3, was reported (Pushkin A, Abuladze N, Lee I, Newman D, Hwang J, Kurtz I. J Biol Chem 274:16569–16575, 1999). We therefore have two distinct NBC-3 isoforms. To prevent any confusion, they are named kNBC-3 (reference 85) and mNBC-3 (Pushkin et al, see above). mNBC-3 is expressed only in myocytes and myocardium. kNBC-3 (reference 85) is the isoform expressed in kidney and other tissues. The term "NBC-3" used in this article refers to kNBC-3.1At the time this paper was under review, the cloning of a new NBC isoform, which is also called NBC-3, was reported (Pushkin A, Abuladze N, Lee I, Newman D, Hwang J, Kurtz I. J Biol Chem 274:16569–16575, 1999). We therefore have two distinct NBC-3 isoforms. To prevent any confusion, they are named kNBC-3 (reference 85) and mNBC-3 (Pushkin et al, see above). mNBC-3 is expressed only in myocytes and myocardium. kNBC-3 (reference 85) is the isoform expressed in kidney and other tissues. The term "NBC-3" used in this article refers to kNBC-3. Functional and molecular studies indicate the presence of all three NBC isoforms in the kidney. All are presumed to mediate the cotransport of Na+ and HCO3- under normal conditions and may be functionally altered in certain pathophysiologic states. Specifically, NBC-1 may be up-regulated in metabolic acidosis and potassium depletion and in response to glucocorticoid excess and may be down-regulated in response to HCO3- loading or alkalosis. Recent studies provide molecular evidence indicating the expression of NBC-1 in pancreatic duct cells. NBC is activated by cystic fibrosis transmembrane conductance regulator (CFTR) and plays an important role in HCO3- secretion in the agonist-stimulated state in pancreatic duct cells. The purpose of this review is to summarize recent functional and molecular studies on the regulation of NBCs in physiologic and pathophysiologic states. Possible signals responsible for the regulation of NBCs in these conditions are examined. Furthermore, the possible role of this transporter in acid-base disorders (such as proximal renal tubular acidosis) is discussed. Proximal tubular acidification processes are primarily responsible for reabsorption of most of the bicarbonate present in glomerular filtrate. The vast bulk of this reabsorption occurs via trans-cellular coupling of the luminal Na+/H+ exchanger NHE-3 and H+-ATPase1Mahnensmith R.L. Aronson P.S. The plasma membrane sodium-hydrogen exchanger and its role physiological and pathophysiological processes.Circ Res. 1985; 56: 773-788Crossref PubMed Scopus (444) Google Scholar, 2Alpern R.J. Cell mechanisms of proximal tubule acidification.Physiol Rev. 1990; 70: 79-114Crossref PubMed Scopus (182) Google Scholar, 3Krapf R. Alpern R.J. Cell pH and transepithelial H/HCO3– transport in the renal proximal tubule.J Membr Biol. 1993; 131: 1-10Crossref PubMed Scopus (52) Google Scholar, 4Soleimani M. Singh G. Physiologic and molecular aspects of the Na+/H+ exchangers in health and disease processes.J Invest Med. 1995; 43: 419-430PubMed Google Scholar with the basolateral Na+:HCO3- cotransporter (NBC)5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar, 6Boron W.F. Boulpaep E.L. The electrogenic Na/HCO3 cotransporter.Kidney Int. 1989; 36: 392-402Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7Aronson P.S. Soleimani M. Grassl S.M. Properties of the renal Na+-HCO3– cotransporter.Semin Nephrol. 1991; 11: 28-36PubMed Google Scholar, 8Soleimani M. Bizal G. Hattabaugh Y. Aronson P.S. Bergman J. Acute regulation of Na+:HCO3– cotransporter system in kidney proximal tubules.Molecular and Cellular Mechanisms of H+ Transport. edited by Hirst BH. Springer-Verlag, Berlin1994Crossref Google Scholar. Although NBC was first described in the kidney proximal tubule, recent studies have shown its presence in numerous types of cells, including brain, liver, colon, cornea, heart, and lung9Astion M.L. Obaid A.L. Orkand R.K. Effects of barium and bicarbonate on glial cells of necturus optic nerve.J Gen Physiol. 1989; 93: 731-744Crossref PubMed Scopus (31) Google Scholar, 10Fitz J.C. Persico M. Scharschmidt B.F. Electrophysiological evidence for Na-coupled bicarbonate transport in cultured rat hepatocyte.Am J Physiol. 1989; 256: G491-G500PubMed Google Scholar, 11Gleeson D. Smith N.D. Boyer J.L. Bicarbonate dependent and independent intracellular pH regulatory mechanisms in rat hepatocyte.J Clin Invest. 1989; 84: 312-321Crossref PubMed Scopus (94) Google Scholar, 12Rajendran V.M. Oesterlin M. Binder H.J. Sodium uptake across basolateral membrane of rat distal colon: Evidence for Na-H exchange and Na-anion cotransport.J Clin Invest. 1991; 88: 1379-1385Crossref PubMed Scopus (53) Google Scholar, 13Jentch T.J. Stahlknecht T.R. Hollwede H. Fischer D.G. Keller S.K. Wiederholt M. A bicarbonate-dependent process inhibitable by disulfonic stilbenes and a Na+/H+ exchanger mediate 22Na+ uptake into cultured bovine corneal endothelium.J Biol Chem. 1985; 260: 795-801Google Scholar, 14Lagadic-Gossmann D. Buckler K.J. Vaughn-Jones R.D. Role of HCO3– in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte.J Physiol (Lond). 1992; 458: 361-384Crossref Scopus (210) Google Scholar, 15Camilion Hurtado M.C. Alvarez B.V. Perez N.G. Cingolini N.E. Role of an electrogenic Na+/HCO3– cotransport in determining myocardial pHi after an increase in heart rate.Circ Res. 1996; 79: 698-704Crossref Scopus (48) Google Scholar, 16Lubman R.L. Chao D.C. Grandall E.D. Basolateral localization of Na-HCO3– cotransporter in alveolar epithelial cells.Respir Physiol. 1995; 100: 15-24https://doi.org/10.1016/0034-5687(94)00114-fCrossref PubMed Google Scholar, suggesting that this pathway plays an important role in mediating HCO3- transport in both epithelial as well as nonepithelial cells. Functional data support the presence of more than one NBC isoform, as judged by direction and stoichiometry of the transporter. In kidney proximal tubule, NBC activity leads to cell acidification, whereas in other tissues (liver and heart), its function leads to cell alkalinization. Furthermore, NBC has a stoichiometry of three equivalents of HCO3- per Na+ ion in the kidney but shows a stoichiometry of 2 HCO3- per Na+ in other tissues. In addition to the NBC, a Na-dependent Cl-/HCO3- exchanger is also expressed in kidney (and certain other tissues) and is shown to be involved in cell pH regulation3Krapf R. Alpern R.J. Cell pH and transepithelial H/HCO3– transport in the renal proximal tubule.J Membr Biol. 1993; 131: 1-10Crossref PubMed Scopus (52) Google Scholar,5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar. The Na-dependent Cl-/HCO3- exchanger is an electroneutral transporter and mediates transport of Na+ and HCO3- into the cell in exchange for cell Cl-3Krapf R. Alpern R.J. Cell pH and transepithelial H/HCO3– transport in the renal proximal tubule.J Membr Biol. 1993; 131: 1-10Crossref PubMed Scopus (52) Google Scholar,5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar. This transporter is likely to be structurally related to NBC-1, based on functional data showing transport of both HCO3- and Na+, and sensitivity to 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS)3Krapf R. Alpern R.J. Cell pH and transepithelial H/HCO3– transport in the renal proximal tubule.J Membr Biol. 1993; 131: 1-10Crossref PubMed Scopus (52) Google Scholar,5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar. Although much information has been gathered on the molecular properties and gene regulation of N+/H+ exchanger (NHE) and anion exchanger (AE) isoforms, molecular properties of Na-coupled HCO3- transporters (gene structure and regulation) have not been characterized. This has been due to the lack of information on the genes encoding these transporters. Recent molecular cloning experiments have identified the presence of several NBC isoforms. These isoforms display distinct tissue distribution patterns and are differentially regulated in certain pathophysiologic states. Although characterization of NBC isoforms is still in its early stage, much information has been gathered about tissue-specific NBCs. The proximal tubule NBC has been characterized with respect to electrogenicity and stoichiometry, ionic base species, cation and anion specificity, inhibitor profile, pH sensitivity, and functional and molecular regulation in acute and chronic states. These aspects are discussed in the following sections. Furthermore, we discuss the characterization of NBC isoforms and their regulation in pathophysiologic disorders. Based on the electrochemical gradients of Na+ and HCO3- across the basolateral membrane (BLM) of the kidney proximal tubule, there should be a net flux of HCO3- from blood to the proximal tubule cell if NBC carries one Na+ for one HCO3-. However, in all studies to date, NBC has been found to be electrogenic and associated with a net flux of negative charge5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar, 6Boron W.F. Boulpaep E.L. The electrogenic Na/HCO3 cotransporter.Kidney Int. 1989; 36: 392-402Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7Aronson P.S. Soleimani M. Grassl S.M. Properties of the renal Na+-HCO3– cotransporter.Semin Nephrol. 1991; 11: 28-36PubMed Google Scholar, 8Soleimani M. Bizal G. Hattabaugh Y. Aronson P.S. Bergman J. Acute regulation of Na+:HCO3– cotransporter system in kidney proximal tubules.Molecular and Cellular Mechanisms of H+ Transport. edited by Hirst BH. Springer-Verlag, Berlin1994Crossref Google Scholar, 9Astion M.L. Obaid A.L. Orkand R.K. Effects of barium and bicarbonate on glial cells of necturus optic nerve.J Gen Physiol. 1989; 93: 731-744Crossref PubMed Scopus (31) Google Scholar, 10Fitz J.C. Persico M. Scharschmidt B.F. Electrophysiological evidence for Na-coupled bicarbonate transport in cultured rat hepatocyte.Am J Physiol. 1989; 256: G491-G500PubMed Google Scholar, 11Gleeson D. Smith N.D. Boyer J.L. Bicarbonate dependent and independent intracellular pH regulatory mechanisms in rat hepatocyte.J Clin Invest. 1989; 84: 312-321Crossref PubMed Scopus (94) Google Scholar, 12Rajendran V.M. Oesterlin M. Binder H.J. Sodium uptake across basolateral membrane of rat distal colon: Evidence for Na-H exchange and Na-anion cotransport.J Clin Invest. 1991; 88: 1379-1385Crossref PubMed Scopus (53) Google Scholar, 13Jentch T.J. Stahlknecht T.R. Hollwede H. Fischer D.G. Keller S.K. Wiederholt M. A bicarbonate-dependent process inhibitable by disulfonic stilbenes and a Na+/H+ exchanger mediate 22Na+ uptake into cultured bovine corneal endothelium.J Biol Chem. 1985; 260: 795-801Google Scholar, 14Lagadic-Gossmann D. Buckler K.J. Vaughn-Jones R.D. Role of HCO3– in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte.J Physiol (Lond). 1992; 458: 361-384Crossref Scopus (210) Google Scholar, 15Camilion Hurtado M.C. Alvarez B.V. Perez N.G. Cingolini N.E. Role of an electrogenic Na+/HCO3– cotransport in determining myocardial pHi after an increase in heart rate.Circ Res. 1996; 79: 698-704Crossref Scopus (48) Google Scholar, 16Lubman R.L. Chao D.C. Grandall E.D. Basolateral localization of Na-HCO3– cotransporter in alveolar epithelial cells.Respir Physiol. 1995; 100: 15-24https://doi.org/10.1016/0034-5687(94)00114-fCrossref PubMed Google Scholar. Boron and Boulpaep found that transport of HCO3- across the BLM of amphibian proximal tubule was associated with a net movement of negative charge in the same direction17Boron W.F. Boulpaep E.L. Intracellular pH regulation in the renal proximal tubule of the salamander: Basolateral HCO3– transport.J Gen Physiol. 1983; 81: 53-94Crossref PubMed Scopus (375) Google Scholar. Similarly, Yoshitomi, Burckhardt and Fromter18Yoshitomi K. Burckhardt B.-C. Fromter E. Rheogenic sodium-bicarbonate co-transport in the peritubular cell membrane of rat renal proximal tubule.Pflügers Arch. 1985; 405: 360-366Crossref PubMed Scopus (202) Google Scholar, and Alpern19Alpern R.J. Mechanism of basolateral membrane H+/OH–/HCO3– transport in the rat proximal convoluted tubule: A sodium-coupled electrogenic process.J Gen Physiol. 1985; 86: 613-636Crossref PubMed Scopus (185) Google Scholar showed that in mammalian proximal tubule cell, NBC is an electrogenic pathway and carries a net negative charge. Grassl and Aronson showed that in the presence of CO2/HCO3- buffer and in the absence of an initial HCO3- gradient, Na+ influx was stimulated in BLM vesicles when an inside positive membrane potential was imposed using an inward K+ gradient and the K+ ionophore valinomycin20Grassl S.M. Aronson P.S. Na+/HCO3– cotransport in basolateral membrane vesicles isolated from rabbit renal cortex.J Biol Chem. 1986; 261: 8778-8783Abstract Full Text PDF PubMed Google Scholar. These observations indicate that the stoichiometry of the cotransport process must involve more than 1 HCO3- per Na+. Knowledge of the precise stoichiometry is important for predicting the direction of net transport under physiologic and pathophysiologic conditions. The greater the HCO3- per Na+ stoichiometry, and hence the greater the net negative charge movement per transport event, the more effectively the inside-negative membrane potential of the cell can drive the net exit of HCO3- against the Na+ and HCO3- gradients. For example, recent measurements18Yoshitomi K. Burckhardt B.-C. Fromter E. Rheogenic sodium-bicarbonate co-transport in the peritubular cell membrane of rat renal proximal tubule.Pflügers Arch. 1985; 405: 360-366Crossref PubMed Scopus (202) Google Scholar indicate that the membrane potential would not be sufficient to drive net HCO3- efflux across the BLM of the proximal tubule cell under physiologic conditions if the stoichiometry of cotransport were only 2 HCO3-:Na+. Two separate studies in perfused rat proximal tubule and in rabbit BLM vesicles showed that NBC has an apparent stoichiometry of 3 HCO3- per Na+ ion18Yoshitomi K. Burckhardt B.-C. Fromter E. Rheogenic sodium-bicarbonate co-transport in the peritubular cell membrane of rat renal proximal tubule.Pflügers Arch. 1985; 405: 360-366Crossref PubMed Scopus (202) Google Scholar,21Soleimani M. Grassl S.M. Aronson P.S. Stoichiometry of the Na+-HCO3– co-transporter in basolateral membrane vesicles isolated from rabbit renal cortex.J Clin Invest. 1987; 79: 1276-1280Crossref PubMed Scopus (127) Google Scholar. With such a stoichiometry, the inside-negative membrane potential, normally on the order of -60 mV, is sufficient to drive HCO3- exit against the inward concentration gradients of HCO3- and Na+ that are present across the BLM of the intact proximal tubule cell. It should be emphasized that although the results of these studies are consistent with a stoichiometry of 3 HCO3- per Na+ ion, they are equally consistent with any transport process in which there is the net transfer of three equivalents of base and one Na. Thus, for example, the cotransport of Na+ with 3 HCO3-, the cotransport of Na+ with 2 HCO3- and 1 OH- and/or cotransport of Na+ with 1 HCO3- and 1 CO3= are thermodynamically equivalent processes. The nature of the base species transported via NBC was studied by 22Na influx method in BLM vesicles isolated from rabbit renal cortex22Soleimani M. Aronson P.S. Ionic mechanism of Na+-HCO3– cotransport in rabbit renal basolateral membrane vesicles.J Biol Chem. 1989; 264: 18302-18308Abstract Full Text PDF PubMed Google Scholar. The results showed that 22Na influx was stimulated when [CO3=] was increased at constant [HCO3-], indicating the existence of a transport site for CO3=. The results further showed that the binding of HCO3- to a distinct site is essential for the binding of CO3= to its site22Soleimani M. Aronson P.S. Ionic mechanism of Na+-HCO3– cotransport in rabbit renal basolateral membrane vesicles.J Biol Chem. 1989; 264: 18302-18308Abstract Full Text PDF PubMed Google Scholar. Based on these studies, it was concluded that the HCO3- exit across the BLM of the kidney proximal tubule occurs via a cotransport of 1Na+:1CO3=:1HCO3- on separate distinct sites22Soleimani M. Aronson P.S. Ionic mechanism of Na+-HCO3– cotransport in rabbit renal basolateral membrane vesicles.J Biol Chem. 1989; 264: 18302-18308Abstract Full Text PDF PubMed Google Scholar, consistent with a stoichiometry of three equivalents of base per Na21Soleimani M. Grassl S.M. Aronson P.S. Stoichiometry of the Na+-HCO3– co-transporter in basolateral membrane vesicles isolated from rabbit renal cortex.J Clin Invest. 1987; 79: 1276-1280Crossref PubMed Scopus (127) Google Scholar. NBC is expressed in several mammalian cell types, including epithelial as well as nonepithelial cells. A major difference with respect to the functional mode of the NBC in kidney and other tissues is its direction of transport. In kidney proximal tubule cells, this transporter mediates the exit of HCO3- from the cell to the blood5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar, 6Boron W.F. Boulpaep E.L. The electrogenic Na/HCO3 cotransporter.Kidney Int. 1989; 36: 392-402Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7Aronson P.S. Soleimani M. Grassl S.M. Properties of the renal Na+-HCO3– cotransporter.Semin Nephrol. 1991; 11: 28-36PubMed Google Scholar, 8Soleimani M. Bizal G. Hattabaugh Y. Aronson P.S. Bergman J. Acute regulation of Na+:HCO3– cotransporter system in kidney proximal tubules.Molecular and Cellular Mechanisms of H+ Transport. edited by Hirst BH. Springer-Verlag, Berlin1994Crossref Google Scholar, whereas in other epithelial cells and certain nonepithelial cells such as heart14Lagadic-Gossmann D. Buckler K.J. Vaughn-Jones R.D. Role of HCO3– in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte.J Physiol (Lond). 1992; 458: 361-384Crossref Scopus (210) Google Scholar,15Camilion Hurtado M.C. Alvarez B.V. Perez N.G. Cingolini N.E. Role of an electrogenic Na+/HCO3– cotransport in determining myocardial pHi after an increase in heart rate.Circ Res. 1996; 79: 698-704Crossref Scopus (48) Google Scholar and liver10Fitz J.C. Persico M. Scharschmidt B.F. Electrophysiological evidence for Na-coupled bicarbonate transport in cultured rat hepatocyte.Am J Physiol. 1989; 256: G491-G500PubMed Google Scholar,11Gleeson D. Smith N.D. Boyer J.L. Bicarbonate dependent and independent intracellular pH regulatory mechanisms in rat hepatocyte.J Clin Invest. 1989; 84: 312-321Crossref PubMed Scopus (94) Google Scholar, this transporter mediates the entry of HCO3- from blood to the cell. As such, in the kidney proximal tubule, NBC functions as an acid loader, because its direction of transport leads to cell acidification. However, in heart or liver, NBC functions as an alkaline loader, because its direction of transport leads to cell alkalinization. Furthermore, the kidney NBC has a stoichiometry of three base equivalents per 1 Na, whereas the brain NBC has a stoichiometry of two base equivalents per Na5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar, 6Boron W.F. Boulpaep E.L. The electrogenic Na/HCO3 cotransporter.Kidney Int. 1989; 36: 392-402Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7Aronson P.S. Soleimani M. Grassl S.M. Properties of the renal Na+-HCO3– cotransporter.Semin Nephrol. 1991; 11: 28-36PubMed Google Scholar, 8Soleimani M. Bizal G. Hattabaugh Y. Aronson P.S. Bergman J. Acute regulation of Na+:HCO3– cotransporter system in kidney proximal tubules.Molecular and Cellular Mechanisms of H+ Transport. edited by Hirst BH. Springer-Verlag, Berlin1994Crossref Google Scholar. Heart NBC is either electroneutral14Lagadic-Gossmann D. Buckler K.J. Vaughn-Jones R.D. Role of HCO3– in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte.J Physiol (Lond). 1992; 458: 361-384Crossref Scopus (210) Google Scholar or has a stoichiometry of 2 bases per Na15Camilion Hurtado M.C. Alvarez B.V. Perez N.G. Cingolini N.E. Role of an electrogenic Na+/HCO3– cotransport in determining myocardial pHi after an increase in heart rate.Circ Res. 1996; 79: 698-704Crossref Scopus (48) Google Scholar, perhaps depending on the myocardial cell type. Whether the difference in the direction of NBC movement in kidney and other tissues is due to differences in the membrane potential or cell ionic compositions in these tissues or whether it suggests the presence of other isoforms of this transporter has been the subject of intense speculation. Recent molecular studies illustrate that the proximal tubule NBC23Burnham C.E. Amlal H. Wang Z. Shull G.E. Soleimani M. Cloning and functional expression of a human kidney Na+:HCO3– cotransporter.J Biol Chem. 1997; 272: 19111-19114Crossref PubMed Scopus (168) Google Scholar, 24Romero M.F. Hediger M.A. Boulpaep E.L. Boron W.F. Expression cloning and characterization of a renal electrogenic Na+:HCO3– cotransporter.Nature. 1997; 387: 409-413Crossref PubMed Scopus (362) Google Scholar, 25Burnham C.E. Flagella M. Wang Z. Amlal H. Shull G.H. Soleimani M. Cloning, renal distribution, and regulation of the rat Na+-HCO3– cotransporter.Am J Physiol. 1998; 274: F1119-F1126PubMed Google Scholar, 26Romero M.F. Fong P. Berger U.V. Hediger M.A. Boron W.F. Cloning and functional expression of rNBC, an electrogenic Na+-HCO3– cotransporter.Am J Physiol. 1998; 274: F425-F432PubMed Google Scholar, 27Abuldaze N. Lee I. Newman D. Hwang J. Pushkin A. Kurtz I. Axial heterogeneity of sodium-bicarbonate cotransporter expression in the rabbit proximal tubule.Am J Physiol. 1998; 274: F628-F633Google Scholar is distinct from the cardiac NBC, indicating that the opposite functional modes of cotransport (influx in the cardiac cells and efflux in the kidney cells) are likely because of the presence of two different isoforms in these tissues. A comparison of the studies in kidney and pancreas, however, indicates that the same NBC isoform can work in opposite directions in two different tissues. For example, NBC-1 is expressed in both kidney proximal tubule25Burnham C.E. Flagella M. Wang Z. Amlal H. Shull G.H. Soleimani M. Cloning, renal distribution, and regulation of the rat Na+-HCO3– cotransporter.Am J Physiol. 1998; 274: F1119-F1126PubMed Google Scholar, 26Romero M.F. Fong P. Berger U.V. Hediger M.A. Boron W.F. Cloning and functional expression of rNBC, an electrogenic Na+-HCO3– cotransporter.Am J Physiol. 1998; 274: F425-F432PubMed Google Scholar, 27Abuldaze N. Lee I. Newman D. Hwang J. Pushkin A. Kurtz I. Axial heterogeneity of sodium-bicarbonate cotransporter expression in the rabbit proximal tubule.Am J Physiol. 1998; 274: F628-F633Google Scholar and pancreatic duct cells28Abdulazade N. Lee I. Newman D. Hwang J. Boorer K. Pushkin A. Kurtz I. Molecular cloning, chromosomal localisation, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter.J Biol Chem. 1998; 273: 17689-17695Crossref PubMed Scopus (220) Google Scholar,29Shumaker H. Amlal H. Frizzell R. Ulrich II, Cd Soleimani M. CFTR drives Na+-nHCO3– cotransport in pancreatic duct cells: A basis for defective HCO3– secretion in CF.Am J Physiol. 1999; 276: C16-C25PubMed Google Scholar; however, it works in the influx mode in the pancreatic duct cells29Shumaker H. Amlal H. Frizzell R. Ulrich II, Cd Soleimani M. CFTR drives Na+-nHCO3– cotransport in pancreatic duct cells: A basis for defective HCO3– secretion in CF.Am J Physiol. 1999; 276: C16-C25PubMed Google Scholar but operates in the efflux mode in the kidney proximal tubule5Preisig P.A. Alpern R.J. Basolateral membrane H-OH-HCO3– transport in the proximal tubule.Am J Physiol. 1989; 256: F751-F756PubMed Google Scholar, 6Boron W.F. Boulpaep E.L. The electrogenic Na/HCO3 cotransporter.Kidney Int. 1989; 36: 392-402Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7Aronson P.S. Soleimani M. Grassl S.M. Properties of the renal Na+-HCO3– cotransporter.Semin Nephrol. 1991; 11: 28-36PubMed Google Scholar, 8Soleimani M. Bizal G. Hattabaugh Y. Aronson P.S. Bergman J. Acute regulation of Na+:HCO3– cotransporter system in kidney proximal tubules.Molecular and Cellular Mechanisms of H+ Transport. edited by Hirst BH. Springer-Verlag, Berlin1994Crossref Google Scholar. This is due to a depolarized membrane potential in the pancreatic duct cells, which results from CFTR activation with subsequent Cl- secretion30Case R.M. Argent B.E. Pancreatic duct cell secretion: Control and mechanisms of transport.in: Go L.W. The Pancreas: Biology, Pathobiology, and Disease. 2nd ed. Raven Press, New York1993: 301-350Google Scholar. The schematic diagram in Figure 1 illustrates the modes and directions of operation of the NBC in kidney proximal tubule cells, pancreatic duct cells, and hepatocytes. Cation and anion specificity of NBC has been studied in cortical BLM vesicles. Li+ was the only other cation tested that showed any significant affinity for the cotransporter22Soleimani M. Aronson P.S. Ionic mechanism of Na+-HCO3– cotransport in rabbit renal basolateral membrane vesicles.J Biol Chem. 1989; 264: 18302-18308Abstract Full Text PDF PubMed Google Scholar,31Soleimani M. Lesoine G.A. Bergman J.A. Aronson P.S. Cation specificity and modes of the Na+:CO3=:HCO3– cotransporter in renal basolateral membrane vesicles.J Biol Chem. 1991; 266: 8706-8710Abstract Full Text PDF PubMed Google Scholar. However, the affinity for Li+ was one fifth of that for Na+22Soleimani M. Aronson P.S. Ionic mechanism of Na+-HCO3– cotransport in rabbit renal basolateral membrane vesicles.J Biol Chem. 1989; 264: 18302-18308Abstract Full Text PDF PubMed Google Scholar. In the presence of CO2/HCO3- and the absence of initial pH and HCO3- gradients, the BLM vesicles loaded with Li+ showed intracellular acidification31Soleimani M. Lesoine G.A. Bergman J.A. Aronson P.S. Cation specificity and modes of the Na+:CO3=:HCO3– cotransporter in renal basolateral membrane vesicles.J Biol Chem. 1991; 266: 8706-8710Abstract Full Text PDF PubMed Google Scholar. This Li+-dependent HCO3- ef
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