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Journal of Biomedicine and Biotechnology
Volume 2010 (2010), Article ID 238080, 10 pages
Mechanisms of the Regulation of the Intestinal Exchanger NHE3
1Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
2Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA
Received 21 July 2009; Accepted 11 September 2009
Academic Editor: Kenichiro Kitamura
Copyright © 2010 Peijian He and C. Chris Yun. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A major of absorptive process in the proximal part of intestine and kidney is electroneutral exchange of and by exchanger type 3 (NHE3). During the past decade, significant advance has been achieved in the mechanisms of NHE3 regulation. A bulk of the current knowledge on exchanger regulation is based on heterologous expression of mammalian exchangers in exchanger deficient fibroblasts, renal epithelial, and intestinal epithelial cells. Based on the reductionist's approach, an understanding of NHE3 regulation has been greatly advanced. More recently, confirmations of in vitro studies have been made using animals deficient in one or more proteins but in some cases unexpected findings have emerged. The purpose of this paper is to provide a brief overview of recent progress in the regulation and functions of NHE3 present in the luminal membrane of the intestinal tract.
The primary non-motor function of the intestine is absorption. The human intestine absorbs 8.6–9 L of electrolyte-rich fluid per day. This seems small compared to the kidney, which filters about 180 L of fluid per day. The conventional dogma is that the absorption of water results principally from the osmotic gradient created across the epithelium by absorption of electrolytes and nutrients. Water flux can occur through the paracellular and transcellular routes, but the large surface area of the brush border membrane aided by the presence of aquaporin water channels favors the transcellular water flux .
The process of exchange is present in all organisms from single cell bacteria to multicellular organisms . exchanger type 3, NHE3 (SLC9A3), is highly expressed at the apical membrane of the small intestine, colon, and proximal tubules of the kidney. In the intestine and colon, NHE3 plays a major role in transepithelial absorption of and water. Apart from NHE3, other contributors to and water absorption include the epithelial channel that is predominantly expressed in the colon and -coupled cotransporters, such as -glucose cotransporter and -coupled amino acid transporters.
In the intestinal tract, NHE3 is often functionally coupled to the exchanger DRA (downregulated in adenoma; SLC26A3) or PAT1 (putative anion transporter1; SLC26A6) mediates electroneutral NaCl absorption . In the kidney, NHE3 is the main exchanger expressed at the apical membrane of the proximal tubule but also located at the apical membrane of the thick ascending and thin descending limbs of Henle [4, 5]. In the proximal tubule, NHE3 is coupled with a /base exchanger, -formate or -oxalate exchanger [6, 7] and accounts for approximately 50% of the NaCl and 70% of the reabsorption from the glomerular filtrate [8, 9]. In addition to its role in and water absorption, NHE3 modulates the absorption of other nutrients, such as dipeptides and amino acids, by creating an -gradient [10, 11]. Conversely, short-chain fatty acids activate NHE3 as well as NHE2 activity by the cellular acidification [12, 13].
To date, 9 mammalian exchangers have been identified at molecular level (Table 1). All the mammalian exchangers share similarities in size (between 645 and 898 amino acids) and the secondary structure with two structurally and functionally distinct domains: an N-terminal domain with 12 transmembrane helices and an equally large C-terminal cytoplasmic domain [3, 14–16]. The conservation of amino acid residues among the exchangers is significantly greater along the N-terminal membranous domain (50–60%) than the C-terminal cytoplasmic domain (20–23%). The N-terminal domain functions in ion transport; whereas the C-terminal domain determines the regulatory nature of the exchanger . The divergence in this C-terminal region is likely to reflect the differences in kinase regulation among different exchangers.
2. / Exchangers in the Intestinal Tract
Four exchangers in the intestinal tract, NHE1-3 and NHE8, are located on the plasma membrane of intestinal epithelial cells (Figure 1) [18–20]. NHE1, NHE2, and NHE3 are most abundantly expressed in the plasma membrane of epithelial cells in the intestinal tract. NHE1 (SLC9A1) is the first exchanger cloned in 1989 and is ubiquitously expressed in all cells where it is a primary regulator of pH homeostasis and cell volume regulation [14, 21]. In addition, the roles of NHE1 as an anchor for actin filaments and a scaffold for signaling molecules have been reported by Barber and others [22–25]. As expected, NHE1-deficient (Nhe1-/-) mice exhibit severe defects, including ataxia, growth retardation, and seizures that are often lethal [26, 27]. However, Nhe1-/- mice do not display a morphological aberration in the intestine, although mild atrophy of the glandular mucosa and a thickening of the lamina propria in the stomach were observed . The absence of a major defect in Nhe1-/- mice appears to suggest that NHE1 does not play a significant role or that a compensatory mechanism probably involving other NHEs makes up for the absence of NHE1, but the functions of NHE1 in the intestine have not been closely scrutinized.
NHE3 is the major exchanger at the apical membrane of surface epithelial cells as supported by a number of studies based on in situ hybridization, immunohistochemical analysis, and a targeted deletion of Nhe3 gene in mouse [19, 28–31]. Genetic disruption of NHE3 expression in mice resulted in modest diarrhea, relatively low blood pressure, and mild metabolic acidosis . However, ablation of NHE3 did not completely inhibit small intestinal salt absorption , suggesting that other absorptive transporters must exist, but their molecular identity is under debate [30, 32, 33].
Primarily due to its presence at the apical membrane of intestinal epithelial cells, NHE2 (SLC9A2) was thought to function in absorption. Quantitative analysis of functional exchange activity in rabbit ileum showed that both NHE2 and NHE3 contribute equally to basal absorption . Moreover, depletion enhanced both NHE2 and NHE3 expression and activities in rat colon further suggesting the role of NHE2 in absorption . However, mice with targeted deletion of Nhe2 gene have a distinctly different phenotype from Nhe3-/- mice . Nhe2-/- mice do not display any morphological defect, and the overall rate of absorption is not affected by the absence of NHE2 in the intestine . A similar result was obtained when NHE2 was pharmacologically inhibited in wild-type intestine , and compound deletion of NHE2 and NHE3 in mice did not increase the severity of diarrhea compared with Nhe3-/- mice . Instead, Nhe2-/- mice develop gastric mucosa atrophy with a severe decrease in the number of mature parietal cells . NHE2 is necessary for long-term viability of parietal cells but is not required for acid secretion by the parietal cells. Hence, despite the high level of NHE2 expression in the intestine and its localization to the brush border membrane of epithelial cells, the physiological role of NHE2 remains elusive. On the other hands, it was shown that the expression of NHE2 is high in mouse colonic crypts and the absence of NHE2 results in upregulation of NHE3 expression at the crypt base, suggesting the role of NHE2 in absorption and regulation in the colonic crypts [30, 38].
NHE4 (SLC9A4), though not present in the intestine or colon , is highly expressed in parietal and chief cells of the stomach . Deletion of Nhe4 in mice resulted in hypochlorhydria with reduced numbers of parietal cells and a loss of mature chief cells .
NHE8 (SLC9A8) is ubiquitously expressed with the highest levels of expression in the kidney, testis, muscle, and liver . Localization of NHE8 in the apical membrane of intestinal epithelia cells was shown, and upregulation of NHE8 mRNA expression in young animals compared with adult animals suggests a possible role of NHE8 in absorption during early development . Similarly, it was shown that NHE8 expression is most abundant in the proximal tubules of neonate rats than in adults, suggesting that NHE8 may account for the -dependent efflux in neonatal proximal tubules . The localization of NHE8 overlaps with that of NHE3 in the intestinal tract and the renal proximal tubules [20, 43], but the relative contribution by NHE8 in absorption remains to be determined. The expression of NHE8 in Nhe3-/- mice was reported, but without a detectable change in the expression level [20, 43]. It has been demonstrated that -dependent secretion in the renal proximal tubules of Nhe3-/- mice is approximately 50% that of wild-type mice and that the residual -dependent secretion is mediated by a previously unrecognized EIPA-sensitive protein secretory mechanisms . Congruently, it was suggested that colonic cryptal -dependent recovery in Nhe2-/- mice is mediated by an EIPA-sensitive but not NHE3-dependent mechanism . Pharmacological characterization of NHE8 in cultured renal epithelial cells has shown its sensitivity to EIPA , but whether NHE8 is responsible for these unidentified EIPA-sensitive transport processes is yet to be determined.
3. Mechanisms of NHE3 Regulation
The activity of NHE3 at the apical membrane of epithelial cells is modulated by a number of mechanisms (Figure 1). These include transcriptional regulation [46–49], protein phosphorylation [50–52], protein-protein interaction [53–55], and trafficking [56–62]. A brief review of some of these pathways will be presented here but the readers can refer to [63–66] for more extensive reviews.
The C-terminal cytoplasmic domain of NHE3 contains multiple putative phosphorylation sites. NHE3 is believed to be phosphorylated by protein kinases as part of the signal transduction that modulates NHE3 activity. Changes in phosphorylation of NHE3 by protein kinase A (PKA) has been demonstrated in vitro using cultured cells as well as in vivo in rat kidney [50, 67, 68]. Specifically, mutation of either Ser-552 or Ser-605 abolished NHE3 inhibition by 8-Br-cAMP that activates PKA . In addition to PKA, our lab showed that the serum- and glucocorticoid-inducible kinase 1 (SGK1) is capable of phosphorylating NHE3 at Ser-665 . Mutation of Ser-665 abrogated NHE3 regulation by glucocorticoids.
The mechanisms by which phosphorylation alters NHE3 activity are not known. It seems likely that phosphorylation modulates NHE3 activity by an allosteric shift induced by the bulky phosphate side chain. However, a study by Kocinsky et al.  showed that there is a temporal dissociation of NHE3 phosphorylation and activity, suggesting that phosphorylation may not directly affect the transport activity of NHE3. Alternatively, phosphorylation of NHE3 may modulate NHE3 subcellular trafficking or interaction with other regulatory proteins. For instance, phosphorylation at Ser-552 and Ser-605 precedes inhibition of NHE3 activity by PKA . In addition, NHE3 basal phosphorylation by casein kinase 2 has been suggested to modulate NHE3 trafficking .
NHE3 differs from other isoforms in that it recycles between the plasma membrane and intracellular compartments . When epitope-tagged NHE3 was stably expressed in NHE-deficient Chinese hamster ovary (CHO) cells, a sizable fraction was found in recycling endosomes , and the plasma membrane NHE3 is endocytosed via a clathrin-mediated pathway . Ectopic expression in Madin-Darby canine kidney (MDCK) cells showed that NHE3 exists in four distinct subcompartments: (i) a virtually immobile subpopulation that is retained on the apical membrane by interaction with the actin cytoskeleton in a manner that depends on the sustained activity of Rho GTPases; (ii) a mobile subpopulation on the apical membrane, which can be readily internalized; (iii)-(iv) two intracellular compartments that can be differentiated by their rate of exchange with the apical pool of NHE3 . McDonough and colleagues have shown through a series of in vivo studies that NHE3 retracts in intact proximal tubules via a two-step process, from villi to the intermicrovillar cleft and then to a higher density membrane pool that appears to serve as a recruitable storage pool [61, 62]. Whether similar trafficking of NHE3 occurs at the brush border membrane of intestinal epithelial cells is not known.
Lipid rafts are discrete membrane domains that are enriched in glycosphingolipids and cholesterol and that are resistant to solubilization in cold Triton X-100 . Studies based on detergent solubility, density gradient, and manipulation of membrane cholesterol content have shown that approximately half of apical membrane NHE3 is localized in lipid rafts and that NHE3 activity and trafficking are lipid rafts dependent [59, 75]. These findings imply that the presence of NHE3 with lipid rafts may be important for the temporal compartmentalization of membrane signaling, trafficking, and transport activity.
3.3. Protein-Protein Interaction
The C-terminal cytoplasmic tail of NHE3 is capable of interacting with a large number of cellular and structural proteins, some of which link NHE3 to the cytoskeletal network. Indeed, NHE3 protein exists as part of a large complex in rabbit ileal brush border membrane . One area of NHE3 regulation that has been subjected to intense studies is the interaction with PDZ (postsynaptic density 95, discs large, and zonula occludens-1) domain-containing scaffold proteins, such as exchanger regulatory factor 1 (NHERF1, SLC9A3R1) and NHERF2 (E3KARP, SLC9A3R2), and more recently with PDZK1 (CAP70/NHERF3) and IKKPP (PDZK2/NHERF4) [49, 52–55, 77–82]. These studies collectively raised the novel paradigm that the activity of NHE3 can be controlled by its state of association with other cellular proteins. Other well-studied interacting proteins include megalin, dipeptidyl peptidase IV, and calcineurin homologous protein [83–85]. In addition, binding of ezrin and phosphlipase C- has been reported [86, 87].
A bulk of NHE3 regulation by NHERF proteins is based on heterologous expression in exchanger-deficient PS120 fibroblasts, opossum kidney (OK) cells, and intestinal Caco-2 cells [53–55, 77, 79, 87, 88]. In most part, there are significant overlaps on the regulation of NHE3 among the cultured cells of different origins. However, studies using mice with targeted deletion of NHERF1 have revealed an unanticipated disparity in the regulation of NHE3 in the kidney versus intestine. For example, the importance of NHERF1 in PKA-dependent inhibition of NHE3 was implicated from the studies based on heterologous expression of NHERF1 in PS120 fibroblasts and OK cells [54, 55, 89]. As expected, Nherf1-/- mice showed defective regulation of NHE3 by 8-br-cAMP in the kidney and cAMP-mediated phosphorylation of NHE3 was impaired [90, 91]. However, Murtazina et al.  found that 8-Br-cAMP-mediated regulation of NHE3 was intact in NHERF1-deficient ileum. Similarly, forskolin-mediated absorption in the jejunum and proximal colon was unaffected by deletion of NHERF1, despite that forskolin-induced HCO3- secretion was abolished in Nherf1-/- duodenum . An additional pathway regulating NHE3 involving EPAC (exchange protein directly activated by cAMP) was identified in the Nherf1-/- ileum [92, 94], but it does not explain the nonobligatory role of NHERF1 in NHE3 regulation in the intestine. On the other hand, forskolin- and Ca2+-mediated inhibition of NHE3 was abolished in Pdzk1-/- colon, suggesting that PKA-dependent regulation of NHE3 in the intestine is facilitated by a different member of NHERF regulatory proteins . Interestingly, the association of PDZK1 and NHE3 was never been determined in cultured cells, and likewise the role of NHERF1 in NHE3 regulation had not been tested in intestinal cells. The expectation that deletion of NHERF1 should abolish PKA-dependent regulation of NHE3 in the kidney and intestine might have been in part due to an assumption that NHE3 regulation in renal and intestinal epithelial cells is similar.
In the face of a growing list of proteins that interact with NHE3, it remains unclear how NHE3 associates with a large number of proteins. We do not fully understand the scope of protein interactions, but emerging data suggest that the interaction between NHE3 and many of these proteins is dynamic. For example, a change in intracellular Ca2+ is associated with inhibition as well as stimulation of NHE3 [96, 97]. The effects of Ca2+ agonists might vary depending on cell types and we recently showed that it is also subjected by the state of NHE3 association with one or more binding partner . In this study (Figure 2), we showed that Ca2+-dependent inhibition of NHE3 mediated by its association with NHERF2 was opposed by the interaction of NHE3 with IRBIT (IP3 receptor binding protein released with IP3), which enhanced translocation of NHE3 to the surface membrane via a mechanism dependent on calmodulin (CaM) and calmodulin-dependent kinase II . Other studies have shown that the protein interaction of NHE3 also varies along the microdomains of the brush border membrane, and the specific interaction determines the functional state of NHE3. For example, the interaction between NHE3 and megalin occurs in intermicrovillar clefts, where megalin-bound NHE3 is inactive [84, 99]. On the contrary, the association of NHE3 with DPPIV occurs predominantly in the microvillar region in which NHE3 is active .
3.4. Transcriptional Regulation
Most of NHE3 regulation in the literatures describes acute regulation that occurs within the time span of minutes to a few hours of cellular activation. Acute regulation is rapid and reversible and often involves changes in phosphorylation, trafficking, and dynamic interaction with regulatory proteins. On the contrary, chronic regulation of NHE3 involves transcriptional and translational modification of NHE3. There is a great deal of information on NHE3 regulation by glucocorticoids, aldosterone, metabolic acidosis, and chronic hyperosmolality [35, 46–48, 79, 100–106]. Moreover, proinflammatory cytokines, such as IFN-γ and TNF-α, enteropatogenic microbial products downregulate NHE3 expression [107–110].
In short, the regulation of NHE3 is complex with a myriad of cellular signals converge onto a single protein at different levels. One prime example of the complex and integrated regulation of NHE3 is the regulation by glucocorticoids that affect NHE3 via multiple pathways that are often overlapping (Figure 3) [49, 52, 79, 112–114]. The major mechanism of NHE3 regulation by glucocorticoids is by genomic regulation of NHE3 resulting in increased NHE3 mRNA level [47, 102, 112]. However, an acute effect of glucocorticoids on / exchange in the absence of a parallel change in NHE3 mRNA abundance led to the identification of SGK1 as a key kinase targeting NHE3 . Scaffolding of NHE3 and SGK1 by NHERF2 facilitates phosphorylation of NHE3 by SGK1 and leads to the translocation of NHE3 to the cell surface [49, 52]. These findings were supported by the study using mice deficient in SGK1 expression, in which glucocorticoid-mediated stimulation of NHE3 activity and NHE3 translocation to the apical membrane of mouse intestine were significantly attenuated .
Is NHE3 More than a Transporter?
NHE3 is thought to mediate bulk of and water absorption by the intestine and colon. NHE3 is a target of proinflammatory cytokines, such as TNF- and INF- [107, 110]. Nhe3-/- mice overexpress INF-γ and INF--inducible genes in the small intestine as part of a homeostatic response to impaired transepithelial absorption. In inflammatory bowel disease (IBD), INF- expression is characteristically elevated . Sullivan et al.  recently demonstrated that the expression level of NHE3 along with NHERFs was decreased in mucosal biopsies of IBD patients and the mouse colon of dextran sodium sulfate (DSS)-induced colitis. Similarly, the characteristic watery diarrhea in collagenous colitis was in part attributed to reduced net NaCl absorption . Microarray analysis of Nhe3-/- mice revealed that, in addition to the genes of ion transporters and ion channels, genes involved in response to stress, inflammation, and chemotaxis were altered . A following study by the same group showed that NHE3 deficiency compromised innate immune response rendering the animals more susceptible to DSS-induced colitis, and the authors suggested a role of NHE3 as a modifier gene . This is not the first case that an / exchanger assumed a role of modifier of other genes. The absence of NHE1 can induce distinct changes at the expression level of several genes in various brain regions . One question that arises from the studies of Nhe3-/- mice is whether the dysregulation of innate immune response in Nhe3-/- mice arises from the decreased NaCl and water uptake or as a secondary response to stress exerted by the absence of NHE3 protein. Or is it possible that some of these changes are related to the ability of NHE3 to interact with structural proteins? For instance, NHE3 is indirectly linked to the junction complexes through its interaction with PDZ-containing proteins such that absence of NHE3 disrupts the intermolecular network, altering the gene expression levels and the barrier function. However, there is yet no report of colitis in mice deficient in NHERF proteins, albeit decreased NHE3 expression was shown [80, 92, 93]. Although the mechanisms underlying the occurrence of colitis in Nhe3-/- mice require further study, these new findings represent a novel paradigm that NHE3 may serve multifunctions in addition to the transepithelial absorption of .
4. Future Directions
The activity of NHE3 is maintained and modulated so as to regulate intracellular volume, pH, and blood pressure. As discussed in this paper, multiple cellular pathways involving phosphorylation, trafficking, and interaction with cellular proteins are integrated to regulate NHE3 activity. Among the mechanisms of NHE3 regulation, the dynamic and coordinated nature of the increasing list of NHE3 interacting proteins should be a subject of future studies. The recent in vivo findings from animals with targeted deletion of a / exchanger or an accessory protein have helped to validate the previous findings, but in some cases several new paradigms have emerged from the in vivo studies. In particular, the findings in nontransport roles of NHE3 add a new dimension to the pathological function of NHE3 and warrant further studies in the roles of NHE3 in diarrhea associated with inflammation.
This work was supported in part by a Grant (DK061418) from the National Institutes of Health. P. He was supported by a postdoctoral fellowship from the American Heart Association.
- S. Nielsen, B. L. Smith, E. I. Christensen, and P. Agre, “Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 15, pp. 7275–7279, 1993.
- C. L. Brett, M. Donowitz, and R. Rao, “Evolutionary origins of eukaryotic sodium/proton exchangers,” American Journal of Physiology, vol. 288, no. 2, pp. C223–C239, 2005.
- N. C. Zachos, M. Tse, and M. Donowitz, “Molecular physiology of intestinal exchange,” Annual Review of Physiology, vol. 67, no. 1, pp. 411–443, 2005.
- D. Biemesderfer, J. Pizzonia, A. Abu-Alfa, et al., “NHE3: a exchanger isoform of renal brush border,” American Journal of Physiology, vol. 265, no. 5, pp. F736–F742, 1993.
- D. Biemesderfer, P. A. Rutherford, T. Nagy, J. H. Pizzonia, A. K. Abu-Alfa, and P. S. Aronson, “Monoclonal antibodies for high-resolution localization of NHE3 in adult and neonatal rat kidney,” American Journal of Physiology, vol. 273, no. 2, pp. F289–F299, 1997.
- P. S. Aronson, “Ion exchangers mediating NaCl transport in the renal proximal tubule,” Cell Biochemistry and Biophysics, vol. 36, no. 2-3, pp. 147–153, 2002.
- P. S. Aronson and G. Giebisch, “Mechanisms of chloride transport in the proximal tubule,” American Journal of Physiology, vol. 273, no. 2, part 2, pp. F179–F192, 1997.
- P. S. Aronson, “Role of ion exchangers in mediating NaCl transport in the proximal tubule,” Kidney International, vol. 49, no. 6, pp. 1665–1670, 1996.
- I. A. Bobulescu and O. W. Moe, “ exchangers in renal regulation of acid-base balance,” Seminars in Nephrology, vol. 26, no. 5, pp. 334–344, 2006.
- H. Daniel, “Molecular and integrative physiology of intestinal peptide transport,” Annual Review of Physiology, vol. 66, no. 1, pp. 361–384, 2004.
- D. T. Thwaites and C. M. H. Anderson, “-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine,” Experimental Physiology, vol. 92, no. 4, pp. 603–619, 2007.
- T. Gonda, D. Maouyo, S. E. Rees, and M. H. Montrose, “Regulation of intracellular pH gradients by identified Na/H exchanger isoforms and a short-chain fatty acid,” American Journal of Physiology, vol. 276, no. 1, part 1, pp. G259–G270, 1999.
- M. W. Musch, C. Bookstein, Y. Xie, J. H. Sellin, and E. B. Chang, “SCFA increase intestinal Na absorption by induction of NHE3 in rat colon and human intestinal C2/bbe cells,” American Journal of Physiology, vol. 280, no. 4, pp. G687–G693, 2001.
- J. Orlowski and S. Grinstein, “Diversity of the mammalian sodium/proton exchanger SLC9 gene family,” Pflügers Archiv European Journal of Physiology, vol. 447, no. 5, pp. 549–565, 2004.
- M. Zizak, M. E. Cavet, D. Bayle, et al., “ exchanger NHE3 has 11 membrane spanning domains and a cleaved signal peptide: topology analysis using in vitro transcription/translation,” Biochemistry, vol. 39, no. 27, pp. 8102–8112, 2000.
- S. Wakabayashi, T. Pang, X. Su, and M. Shigekawa, “A novel topology model of the human exchanger isoform 1,” Journal of Biological Chemistry, vol. 275, no. 11, pp. 7942–7949, 2000.
- C. H. C. Yun, C.-M. Tse, and M. Donowitz, “Chimeric exchangers: an epithelial membrane-bound N-terminal domain requires an epithelial cytoplasmic C-terminal domain for regulation by protein kinases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 23, pp. 10723–10727, 1995.
- C. Bookstein, A. M. DePaoli, Y. Xie, et al., “ exchangers, NHE-1 and NHE-3, of rat intestine. Expression and localization,” Journal of Clinical Investigation, vol. 93, no. 1, pp. 106–113, 1994.
- W. A. Hoogerwerf, S. C. Tsao, O. Devuyst, et al., “NHE2 and NHE3 are human and rabbit intestinal brush-border proteins,” American Journal of Physiology, vol. 270, no. 1, pp. G29–G41, 1996.
- H. Xu, R. Chen, and F. K. Ghishan, “Subcloning, localization, and expression of the rat intestinal sodium-hydrogen exchanger isoform 8,” American Journal of Physiology, vol. 289, no. 1, pp. G36–G41, 2005.
- C. Sardet, A. Franchi, and J. Pouyssegur, “Molecular cloning, primary structure, and expression of the human growth factor-activatable antiporter,” Cell, vol. 56, no. 2, pp. 271–280, 1989.
- O. Aharonovitz, H. C. Zaun, T. Balla, J. D. York, J. Orlowski, and S. Grinstein, “Intracellular pH regulation by exchange requires phosphatidylinositol 4,5-bisphosphate,” Journal of Cell Biology, vol. 150, no. 1, pp. 213–224, 2000.
- T. Pang, X. Su, S. Wakabayashi, and M. Shigekawa, “Calcineurin homologous protein as an essential cofactor for exchangers,” Journal of Biological Chemistry, vol. 276, no. 20, pp. 17367–17372, 2001.
- M. E. Meima, J. R. Mackley, and D. L. Barber, “Beyond ion translocation: structural functions of the sodium-hydrogen exchanger isoform-1,” Current Opinion in Nephrology and Hypertension, vol. 16, no. 4, pp. 365–372, 2007.
- W. Yan, K. Nehrke, J. Choi, and D. L. Barber, “The Nck-interacting kinase (NIK) phosphorylates the exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor,” Journal of Biological Chemistry, vol. 276, no. 33, pp. 31349–31356, 2001.
- S. M. Bell, C. M. Schreiner, P. J. Schultheis, et al., “Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures,” American Journal of Physiology, vol. 276, no. 4, part 1, pp. C788–C795, 1999.
- G. A. Cox, C. M. Lutz, C.-L. Yang, et al., “Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice,” Cell, vol. 91, no. 1, pp. 139–148, 1997.
- C. Bookstein, Y. Xie, K. Rabenau, et al., “Tissue distribution of exchanger isoforms NHE2 and NHE4 in rat intestine and kidney,” American Journal of Physiology, vol. 273, no. 5, pp. C1496–C1505, 1997.
- P. K. Dudeja, D. D. Rao, I. Syed, et al., “Intestinal distribution of human exchanger isoforms NHE-1, NHE- 2, and NHE-3 mRNA,” American Journal of Physiology, vol. 271, no. 3, pp. G483–G493, 1996.
- O. Bachmann, B. Riederer, H. Rossmann, et al., “The exchanger isoform 2 is the predominant NHE isoform in murine colonic crypts and its lack causes NHE3 upregulation,” American Journal of Physiology, vol. 287, no. 1, pp. G125–G133, 2004.
- P. J. Schultheis, L. L. Clarke, P. Meneton, et al., “Renal and intestinal absorptive defects in mice lacking the NHE3 exchanger,” Nature Genetics, vol. 19, no. 3, pp. 282–285, 1998.
- L. R. Gawenis, X. Stien, G. E. Shull, et al., “Intestinal NaCl transport in NHE2 and NHE3 knockout mice,” American Journal of Physiology, vol. 282, no. 5, pp. G776–G784, 2002.
- J. Chu, S. Chu, and M. H. Montrose, “Apical exchange near the base of mouse colonic crypts,” American Journal of Physiology, vol. 283, no. 1, pp. C358–C372, 2002.
- L. Wormmeester, F. Sanchez de Medina, F. Kokke, et al., “Quantitative contribution of NHE2 and NHE3 to rabbit ileal brush-border exchange,” American Journal of Physiology, vol. 274, no. 5, part 1, pp. C1261–C1272, 1998.
- M. Ikuma, M. Kashgarian, H. J. Binder, and V. M. Rajendran, “Differential regulation of NHE isoforms by sodium depletion in proximal and distal segments of rat colon,” American Journal of Physiology, vol. 276, no. 2, part 1, pp. G539–G549, 1999.
- P. J. Schultheis, L. L. Clarke, P. Meneton, et al., “Targeted disruption of the murine exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion,” Journal of Clinical Investigation, vol. 101, no. 6, pp. 1243–1253, 1998.
- C. Ledoussal, A. L. Woo, M. L. Miller, and G. E. Shull, “Loss of the NHE2 exchanger has no apparent effect on diarrheal state of NHE3-deficient mice,” American Journal of Physiology, vol. 281, no. 6, pp. G1385–G1396, 2001.
- Y. Guan, J. Dong, L. Tackett, J. W. Meyer, G. E. Shull, and M. H. Montrose, “NHE2 is the main apical NHE in mouse colonic crypts but an alternative -dependent acid extrusion mechanism is upregulated in NHE2-null mice,” American Journal of Physiology, vol. 291, no. 4, pp. G689–G699, 2006.
- H. Rossmann, T. Sonnentag, A. Heinzmann, et al., “Differential expression and regulation of exchanger isoforms in rabbit parietal and mucous cells,” American Journal of Physiology, vol. 281, no. 2, pp. G447–G458, 2001.
- L. R. Gawenis, J. M. Greeb, V. Prasad, et al., “Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 exchanger,” Journal of Biological Chemistry, vol. 280, no. 13, pp. 12781–12789, 2005.
- S. Goyal, G. Vanden Heuvel, and P. S. Aronson, “Renal expression of novel exchanger isoform NHE8,” American Journal of Physiology, vol. 284, no. 3, pp. F467–F473, 2003.
- A. M. Becker, J. Zhang, S. Goyal, et al., “Ontogeny of NHE8 in the rat proximal tubule,” American Journal of Physiology, vol. 293, no. 1, pp. F255–F261, 2007.
- S. Goyal, S. Mentone, and P. S. Aronson, “Immunolocalization of NHE8 in rat kidney,” American Journal of Physiology, vol. 288, no. 3, pp. F530–F538, 2005.
- J. Y. Choi, M. Shah, M. G. Lee, et al., “Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule,” Journal of Clinical Investigation, vol. 105, no. 8, pp. 1141–1146, 2000.
- J. Zhang, I. A. Bobulescu, S. Goyal, P. S. Aronson, M. G. Baum, and O. W. Moe, “Characterization of exchanger NHE8 in cultured renal epithelial cells,” American Journal of Physiology, vol. 293, no. 3, pp. F761–F766, 2007.
- K. Laghmani, P. Borensztein, P. Ambühl, et al., “Chronic metabolic acidosis enhances NHE-3 protein abundance and transport activity in the rat thick ascending limb by increasing NHE-3 mRNA,” Journal of Clinical Investigation, vol. 99, no. 1, pp. 24–30, 1997.
- C. H. C. Yun, S. Gurubhagavatula, S. A. Levine, et al., “Glucocorticoid stimulation of ileal absorptive cell brush border exchange and association with an increase in message for NHE-3, an epithelial exchanger isoform,” Journal of Biological Chemistry, vol. 268, no. 1, pp. 206–211, 1993.
- M. Baum, M. Amemiya, V. Dwarakanath, R. J. Alpern, and O. W. Moe, “Glucocorticoids regulate NHE-3 transcription in OKP cells,” American Journal of Physiology, vol. 270, no. 1, part 2, pp. F164–F169, 1996.
- D. Wang, H. Zhang, F. Lang, and C. C. Yun, “Acute activation of NHE3 by dexamethasone correlates with activation of SGK1 and requires a functional glucocorticoid receptor,” American Journal of Physiology, vol. 292, no. 1, pp. C396–C404, 2007.
- H. Zhao, M. R. Wiederkehr, L. Fan, R. L. Collazo, L. A. Crowder, and O. W. Moe, “Acute inhibition of Na/H exchanger NHE-3 by cAMP: role of protein kinase a and NHE-3 phosphoserines 552 and 605,” Journal of Biological Chemistry, vol. 274, no. 7, pp. 3978–3987, 1999.
- M. Zizak, G. Lamprecht, D. Steplock, et al., “cAMP-induced phosphorylation and inhibition of exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor,” Journal of Biological Chemistry, vol. 274, no. 35, pp. 24753–24758, 1999.
- D. Wang, H. Sun, F. Lang, and C. C. Yun, “Activation of NHE3 by dexamethasone requires phosphorylation of NHE3 at Ser663 by SGK1,” American Journal of Physiology, vol. 289, no. 4, pp. C802–C810, 2005.
- J. H. Kim, W. Lee-Kwon, J. B. Park, S. H. Ryu, C. H. C. Yun, and M. Donowitz, “-dependent inhibition of exchanger 3 (NHE3) requires an NHE3-E3KARP--actinin-4 complex for oligomerization and endocytosis,” Journal of Biological Chemistry, vol. 277, no. 26, pp. 23714–23724, 2002.
- C. H. C. Yun, S. Oh, M. Zizak, et al., “cAMP-mediated inhibition of the epithelial brush border exchanger, NHE3, requires an associated regulatory protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 7, pp. 3010–3015, 1997.
- G. Lamprecht, E. J. Weinman, and C. H. C. Yun, “The role of NHERF and E3KARP in the cAMP-mediated inhibition of NHE3,” Journal of Biological Chemistry, vol. 273, no. 45, pp. 29972–29978, 1998.
- R. Collazo, L. Fan, M. C. Hu, H. Zhao, M. R. Wiederkehr, and O. W. Moe, “Acute regulation of exchanger NHE3 by parathyroid hormone via NHE3 phosphorylation and dynamin-dependent endocytosis,” Journal of Biological Chemistry, vol. 275, no. 41, pp. 31601–31608, 2000.
- W. Lee-Kwon, K. Kawano, J. W. Choi, J. H. Kim, and M. Donowitz, “Lysophosphatidic acid stimulates brush border exchanger 3 (NHE3) activity by increasing its exocytosis by an NHE3 kinase A regulatory protein-dependent mechanism,” Journal of Biological Chemistry, vol. 278, no. 19, pp. 16494–16501, 2003.
- H. Hayashi, K. Szászi, N. Coady-Osberg, et al., “Inhibition and redistribution of NHE3, the apical exchanger, by Clostridium difficile toxin B,” Journal of General Physiology, vol. 123, no. 5, pp. 491–504, 2004.
- S. Akhter, O. Kovbasnjuk, X. Li, et al., “ exchanger 3 is in large complexes in the center of the apical surface of proximal tubule-derived OK cells,” American Journal of Physiology, vol. 283, no. 3, pp. C927–C940, 2002.
- X. Li, T. Galli, S. Leu, et al., “ exchanger 3 (NHE3) is present in lipid rafts in the rabbit ileal brush border: a role for rafts in trafficking and rapid stimulation of NHE3,” Journal of Physiology, vol. 537, no. 2, pp. 537–552, 2001.
- L. Yang, P. K. K. Leong, J. O. Chen, N. Patel, S. F. Hamm-Alvarez, and A. A. McDonough, “Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity,” American Journal of Physiology, vol. 282, no. 4, pp. F730–F740, 2002.
- L. E. Yang, A. B. Maunsbach, P. K. K. Leong, and A. A. McDonough, “Differential traffic of proximal tubule transporters during hypertension or PTH: NHE3 to base of microvilli vs. NaPi2 to endosomes,” American Journal of Physiology, vol. 287, no. 5, pp. F896–F906, 2004.
- R. T. Alexander and S. Grinstein, “Tethering, recycling and activation of the epithelial sodium-proton exchanger, NHE3,” Journal of Experimental Biology, vol. 212, no. 11, pp. 1630–1637, 2009.
- M. Donowitz and X. Li, “Regulatory binding partners and complexes of NHE3,” Physiological Reviews, vol. 87, no. 3, pp. 825–872, 2007.
- G. Lamprecht and U. Seidler, “The emerging role of PDZ adapter proteins for regulation of intestinal ion transport,” American Journal of Physiology, vol. 291, no. 5, pp. G766–G777, 2006.
- U. Seidler, A. K. Singh, A. Cinar, et al., “The role of the NHERF family of PDZ scaffolding proteins in the regulation of salt and water transport: lessons learned from knockout mice,” Annals of the New York Academy of Sciences, vol. 1165, pp. 249–260, 2009.
- K. Kurashima, F. H. Yu, A. G. Cabado, E. Z. Szabó, S. Grinstein, and J. Orlowski, “Identification of sites required for down-regulation of exchanger NHE3 activity by cAMP-dependent protein kinase: phosphorylation-dependent and -independent mechanisms,” Journal of Biological Chemistry, vol. 272, no. 45, pp. 28672–28679, 1997.
- H. S. Kocinsky, A. C. C. Girardi, D. Biemesderfer, et al., “Use of phospho-specific antibodies to determine the phosphorylation of endogenous exchanger NHE3 at PKA consensus sites,” American Journal of Physiology, vol. 289, no. 2, pp. F249–F258, 2005.
- H. S. Kocinsky, D. W. Dynia, T. Wang, and P. S. Aronson, “NHE3 phosphorylation at serines 552 and 605 does not directly affect NHE3 activity,” American Journal of Physiology, vol. 293, no. 1, pp. F212–F218, 2007.
- R. Sarker, M. Grønborg, B. Cha, et al., “Casein kinase 2 binds to the C terminus of exchanger 3 (NHE3) and stimulates NHE3 basal activity by phosphorylating a separate site in NHE3,” Molecular Biology of the Cell, vol. 19, no. 9, pp. 3859–3870, 2008.
- S. D'Souza, A. Garcia-Cabado, F. Yu, et al., “The epithelial sodium-hydrogen antiporter exchanger 3 accumulates and is functional in recycling endosomes,” Journal of Biological Chemistry, vol. 273, no. 4, pp. 2035–2043, 1998.
- C.-W. Chow, S. Khurana, M. Woodside, S. Grinstein, and J. Orlowski, “The epithelial exchanger, NHE3, is internalized through a clathrin-mediated pathway,” Journal of Biological Chemistry, vol. 274, no. 53, pp. 37551–37558, 1999.
- R. T. Alexander, W. Furuya, K. Szászi, J. Orlowski, and S. Grinstein, “Rho GTPases dictate the mobility of the Na/H exchanger NHE3 in epithelia: role in apical retention and targeting,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 34, pp. 12253–12258, 2005.
- D. A. Brown, “Lipid rafts, detergent-resistant membranes, and raft targeting signals,” Physiology, vol. 21, no. 6, pp. 430–439, 2006.
- R. Murtazina, O. Kovbasnjuk, M. Donowitz, and X. Li, “ exchanger NHE3 activity and trafficking are lipid raft-dependent,” Journal of Biological Chemistry, vol. 281, no. 26, pp. 17845–17855, 2006.
- X. Li, H. Zhang, A. Cheong, et al., “Carbachol regulation of rabbit ileal brush border exchanger 3 (NHE3) occurs through changes in NHE3 trafficking and complex formation and is Src dependent,” Journal of Physiology, vol. 556, no. 3, pp. 791–804, 2004.
- C. H. C. Yun, G. Lamprecht, D. V. Forster, and A. Sidor, “NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border exchanger NHE3 and the cytoskeletal protein ezrin,” Journal of Biological Chemistry, vol. 273, no. 40, pp. 25856–25863, 1998.
- W. Lee-Kwon, D. C. Johns, B. Cha, et al., “Constitutively active phosphatidylinositol 3-kinase and AKT are sufficient to stimulate the epithelial exchanger 3,” Journal of Biological Chemistry, vol. 276, no. 33, pp. 31296–31304, 2001.
- C. H. C. Yun, Y. Chen, and F. Lang, “Glucocorticoid activation of exchanger isoform 3 revisited: the roles of SGK1 and NHERF2,” Journal of Biological Chemistry, vol. 277, no. 10, pp. 7676–7683, 2002.
- J. Hillesheim, B. Riederer, B. Tuo, et al., “Down regulation of small intestinal ion transport in PDZK1- (CAP70/NHERF3) deficient mice,” Pflügers Archiv European Journal of Physiology, vol. 454, no. 4, pp. 575–586, 2007.
- N. C. Zachos, C. Hodson, O. Kovbasnjuk, et al., “Elevated intracellular calcium stimulates NHE3 activity by an IKEPP (NHERF4) dependent mechanism,” Cellular Physiology and Biochemistry, vol. 22, no. 5-6, pp. 693–704, 2008.
- A. K. Singh, B. Riederer, A. Krabbenhöft, et al., “Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice,” Journal of Clinical Investigation, vol. 119, no. 3, pp. 540–550, 2009.
- F. Di Sole, R. Cerull, V. Babich, et al., “Acute regulation of Na/H exchanger NHE3 by adenosine A1 receptors is mediated by calcineurin homologous protein,” Journal of Biological Chemistry, vol. 279, no. 4, pp. 2962–2974, 2004.
- D. Biemesderfer, T. Nagy, B. DeGray, and P. S. Aronson, “Specific association of megalin and the exchanger isoform NHE3 in the proximal tubule,” Journal of Biological Chemistry, vol. 274, no. 25, pp. 17518–17524, 1999.
- A. C. C. Girardi, B. C. Degray, T. Nagy, D. Biemesderfer, and P. S. Aronson, “Association of exchanger isoform NHE3 and dipeptidyl peptidase IV in the renal proximal tubule,” Journal of Biological Chemistry, vol. 276, no. 49, pp. 46671–46677, 2001.
- B. Cha, M. Tse, C. Yun, et al., “The NHE3 juxtamembrane cytoplasmic domain directly binds ezrin: dual role in NHE3 trafficking and mobility in the brush border,” Molecular Biology of the Cell, vol. 17, no. 6, pp. 2661–2673, 2006.
- N. C. Zachos, D. B. van Rossum, X. Li, et al., “Phospholipase C- binds directly to the exchanger 3 and is required for calcium regulation of exchange activity,” Journal of Biological Chemistry, vol. 284, no. 29, pp. 19437–19444, 2009.
- B. Cha, J. H. Kim, H. Hut, et al., “cGMP inhibition of antiporter 3 (NHE3) requires PDZ domain adapter NHERF2, a broad specificity protein kinase G-anchoring protein,” Journal of Biological Chemistry, vol. 280, no. 17, pp. 16642–16650, 2005.
- E. J. Weinman, D. Steplock, M. Donowitz, and S. Shenolikar, “NHERF associations with sodium-hydrogen exchanger isoform 3 (NHE3) and ezrin are essential for cAMP-mediated phosphorylation and inhibition of NHE3,” Biochemistry, vol. 39, no. 20, pp. 6123–6129, 2000.
- R. Cunningham, D. Steplock, F. Wang, et al., “Defective parathyroid hormone regulation of NHE3 activity and phosphate adaptation in cultured NHERF-1-/- renal proximal tubule cells,” Journal of Biological Chemistry, vol. 279, no. 36, pp. 37815–37821, 2004.
- E. J. Weinman, D. Steplock, and S. Shenolikar, “NHERF-1 uniquely transduces the cAMP signals that inhibit sodium-hydrogen exchange in mouse renal apical membranes,” FEBS Letters, vol. 536, no. 1–3, pp. 141–144, 2003.
- R. Murtazina, O. Kovbasnjuk, N. C. Zachos, et al., “Tissue-specific regulation of sodium/proton exchanger isoform 3 activity in exchanger regulatory factor 1 (NHERF1) null mice: cAMP inhibition is differentially dependent on NHERF1 and exchange protein directly activated by cAMP in ileum versus proximal tubule,” Journal of Biological Chemistry, vol. 282, no. 34, pp. 25141–25151, 2007.
- N. Broere, M. Chen, A. Cinar, et al., “Defective jejunal and colonic salt absorption and altered exchanger 3 (NHE3) activity in NHE regulatory factor 1 (NHERF1) adaptor protein-deficient mice,” Pflügers Archiv European Journal of Physiology, vol. 457, no. 5, pp. 1079–1091, 2009.
- K. J. Honegger, P. Capuano, C. Winter, et al., “Regulation of sodium-proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC),” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 3, pp. 803–808, 2006.
- A. Cinar, M. Chen, B. Riederer, et al., “NHE3 inhibition by cAMP and is abolished in PDZ-domain protein PDZK1-deficient murine enterocytes,” Journal of Physiology, vol. 581, no. 3, pp. 1235–1246, 2007.
- M. E. Cohen, J. Wesolek, J. McCullen, et al., “Carbachol- and elevated -induced translocation of functionally active protein kinase C to the brush border of rabbit ileal absorbing cells,” Journal of Clinical Investigation, vol. 88, no. 3, pp. 855–863, 1991.
- T.-S. Chu, Y. Peng, A. Cano, M. Yanagisawa, and R. J. Alpern, “EndothelinB receptor activates NHE-3 by a -dependent pathway in OKP cells,” Journal of Clinical Investigation, vol. 97, no. 6, pp. 1454–1462, 1996.
- D. He, V. Natarajan, R. Stern, et al., “Lysophosphatidic acid-induced transactivation of epidermal growth factor receptor regulates cyclo-oxygenase-2 expression and prostaglandin release via C/EBP in human bronchial epithelial cells,” Biochemical Journal, vol. 412, no. 1, pp. 153–162, 2008.
- D. Biemesderfer, B. DeGray, and P. S. Aronson, “Active (9.6 S) and inactive (21 S) oligomers of NHE3 in microdomains of the renal brush border,” Journal of Biological Chemistry, vol. 276, no. 13, pp. 10161–10167, 2001.
- M. Baum, A. Cano, and R. J. Alpern, “Glucocorticoids stimulate antiporter in OKP cells,” American Journal of Physiology, vol. 264, no. 6, part 2, pp. F1027–F1031, 1993.
- J. H. Cho, M. W. Musch, C. M. Bookstein, R. L. McSwine, K. Rabenau, and E. B. Chang, “Aldosterone stimulates intestinal absorption in rats by increasing NHE3 expression of the proximal colon,” American Journal of Physiology, vol. 274, no. 3, part 1, pp. C586–C594, 1998.
- J. H. Ciio, M. W. Musch, A. M. DePaoli, et al., “Glucocorticoids regulate exchange expression and activity in region- and tissue-specific manner,” American Journal of Physiology, vol. 267, no. 3, pp. C796–C803, 1994.
- P. R. Kiela, Y. S. Guner, H. Xu, J. F. Collins, and F. K. Ghishan, “Age- and tissue-specific induction of NHE3 by glucocorticoids in the rat small intestine,” American Journal of Physiology, vol. 278, no. 4, pp. C629–C637, 2000.
- S. G. Turnamian and H. J. Binder, “Aldosterone and glucocorticoid receptor-specific agonists regulate ion transport in rat proximal colon,” American Journal of Physiology, vol. 258, no. 3, part 1, pp. G492–G498, 1990.
- P. Ambühl, M. Amemiya, P. A. Preisig, O. W. Moe, and R. J. Alpern, “Chronic hyperosmolality increases NHE3 activity in OKP cells,” Journal of Clinical Investigation, vol. 101, no. 1, pp. 170–177, 1998.
- M. Amemiya, Y. Yamaji, A. Cano, O. W. Moe, and R. J. Alpern, “Acid incubation increases NHE-3 mRNA abundance in OKP cells,” American Journal of Physiology, vol. 269, no. 1, part 1, pp. C126–C133, 1995.
- Md. R. Amin, J. Malakooti, R. Sandoval, P. K. Dudeja, and K. Ramaswamy, “IFN- and TNF- regulate human NHE3 gene expression by modulating the Sp family transcription factors in human intestinal epithelial cell line C2BBe1,” American Journal of Physiology, vol. 291, no. 5, pp. C887–C896, 2006.
- A. L. Woo, L. A. Gildea, L. M. Tack, et al., “In vivo evidence for interferon--mediated homeostatic mechanisms in small intestine of the NHE3 exchanger knockout model of congenital diarrhea,” Journal of Biological Chemistry, vol. 277, no. 50, pp. 49036–49046, 2002.
- G. Hecht, K. Hodges, R. K. Gill, et al., “Differential regulation of exchange isoform activities by enteropathogenic E. coli in human intestinal epithelial cells,” American Journal of Physiology, vol. 287, no. 2, pp. G370–G378, 2004.
- F. Rocha, M. W. Musch, L. Lishanskiy, et al., “IFN- downregulates expression of exchangers NHE2 and NHE3 in rat intestine and human Caco-2/bbe cells,” American Journal of Physiology, vol. 280, no. 5, pp. C1224–C1232, 2001.
- P. He, H. Zhang, and C. C. Yun, “IRBIT, inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with IP3, binds exchanger NHE3 and activates NHE3 activity in response to calcium,” Journal of Biological Chemistry, vol. 283, no. 48, pp. 33544–33553, 2008.
- M. Baum, O. W. Moe, D. L. Gentry, and R. J. Alpern, “Effect of glucocorticoids on renal cortical NHE-3 and NHE-1 mRNA,” American Journal of Physiology, vol. 267, no. 3, pp. F437–F442, 1994.
- J. Klisic, M. C. Hu, V. Nief, et al., “Insulin activates exchanger 3: biphasic response and glucocorticoid dependence,” American Journal of Physiology, vol. 283, no. 3, pp. F532–F539, 2002.
- I. A. Bofoulescu, V. Dwarakanath, L. Zou, J. Zhang, M. Baum, and O. W. Moe, “Glucocorticoids acutely increase cell surface exchanger-3 (NHE3) by activation of NHE3 exocytosis,” American Journal of Physiology, vol. 289, no. 4, pp. F685–F691, 2005.
- F. Grahammer, G. Henke, C. Sandu, et al., “Intestinal function of gene-targeted mice lacking serum- and glucocorticoid-inducible kinase 1,” American Journal of Physiology, vol. 290, no. 6, pp. G1114–G1123, 2006.
- S. R. Targan and L. C. Karp, “Defects in mucosal immunity leading to ulcerative colitis,” Immunological Reviews, vol. 206, no. 1, pp. 296–305, 2005.
- S. Sullivan, P. Alex, T. Dassopoulos, et al., “Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD-associated diarrhea,” Inflammatory Bowel Diseases, vol. 15, no. 2, pp. 261–274, 2009.
- N. Bürgel, C. Bojarski, J. Mankertz, M. Zeitz, M. Fromm, and J. Schulzke, “Mechanisms of diarrhea in collagenous colitis,” Gastroenterology, vol. 123, no. 2, pp. 433–443, 2002.
- D. Laubitz, C. B. Larmonier, A. Bai, et al., “Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis,” American Journal of Physiology, vol. 295, no. 1, pp. G63–G77, 2008.
- P. R. Kiela, D. Laubitz, C. B. Larmonier, et al., “Changes in mucosal homeostasis predispose NHE3 knockout mice to increased susceptibility to DSS-induced epithelial injury,” Gastroenterology, vol. 137, no. 3, pp. 965–975, 2009.
- D. Zhou, J. Xue, O. Gavrialov, and G. G. Haddad, “ exchanger 1 deficiency alters gene expression in mouse brain,” Physiological Genomics, vol. 18, no. 3, pp. 331–339, 2004.
- C. M. Tse, A. I. Ma, V. W. Yang, et al., “Molecular cloning and expression of a cDNA encoding the rabbit ileal villus cell basolateral membrane exchanger,” EMBO Journal, vol. 10, no. 8, pp. 1957–1967, 1991.
- J. H. Pizzonia, D. Biemesderfer, A. K. Abu-Alfa, et al., “Immunochemical characterization of exchanger isoform NHE4,” American Journal of Physiology, vol. 275, no. 4, part 2, pp. F510–F517, 1998.
- S. Attaphitaya, K. Park, and J. E. Melvin, “Molecular cloning and functional expression of a rat exchanger (NHE5) highly expressed in brain,” Journal of Biological Chemistry, vol. 274, no. 7, pp. 4383–4388, 1999.
- N. R. Baird, J. Orlowski, E. Z. Szabó, et al., “Molecular cloning, genomic organization, and functional expression of exchanger isoform 5 (NHE5) from human brain,” Journal of Biological Chemistry, vol. 274, no. 7, pp. 4377–4382, 1999.
- N. Nakamura, S. Tanaka, Y. Teko, K. Mitsui, and H. Kanazawa, “Four exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation,” Journal of Biological Chemistry, vol. 280, no. 2, pp. 1561–1572, 2005.
- H. Xu, H. Chen, J. Dong, R. Lynch, and F. K. Ghishan, “Gastrointestinal distribution and kinetic characterization of the sodium-hydrogen exchanger isoform 8 (NHE8),” Cellular Physiology and Biochemistry, vol. 21, no. 1–3, pp. 109–116, 2008.