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SLC9 Gene Family: Function, Expression, and Regulation

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ABSTRACT

The Slc9 family of Na+/H+ exchangers (NHEs) plays a critical role in electroneutral exchange of Na+ and H+ in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na+ and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid‐base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na+/H+ exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na+/H+ exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na+/H+ exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na+/H+ exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555‐583, 2018.

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Figure 1. Figure 1. Simplified model of basolateral and apical electrolyte transport in the (A) acinar and (B) ductal cells of the salivary (parotid) gland. NKCC1, Na‐K‐Cl cotransporter, SLC12A2; NHE1‐4, Na+/H+ exchangers 1 to 4, SLC9A1‐A4; AE2, anion exchanger 2, SLC4A2; CFTR, cystic fibrosis transmembrane conductance regulator; AQP1, aquaporin 1; AQP5, aquaporin 5; NBCe1‐B, major splice variant of the electrogenic Na+/HCO3 cotransporter (NBCe1, SLC4A4); NBCn1, electroneutral sodium/bicarbonate cotransporter, SLC4A7; ENac, electrogenic Na+ channels, SCNN1; KCa1.1 and KCa3.1, calcium‐activated potassium channels, KCNMA1 and KCNN4, respectively. For detailed reviews of the key players and mechanism involved, see Ohana () and Roussa et al. (). Question marks indicate controversial contribution of individual transport proteins.
Figure 2. Figure 2. Simplified model of basolateral and apical electrolyte transport in the (A) acinar and (B) ductal cells of the exocrine pancreas. NHE1, NHE4, Na+/H+ exchangers 1 and 4; SLC9A1 and SLC9A4, respectively; pNBC1, electrogenic Na+/HCO3 cotransporter, SLC4A4, AE2, anion exchanger 2, SLC4A2; CFTR, cystic fibrosis transmembrane conductance regulator; SLC26A6 (apical Cl/HCO3 exchanger). For detailed review of the key players and mechanism involved, see excellent reviews by Steward and Ishiguro (), Steward et al. (), and Ishiguro et al. ()
Figure 3. Figure 3. Simplified cellular model of the role of apical Na+/H+ exchange in transepithelial sodium, glucose, and water absorption in small intestinal epithelial cells. SGLT1, sodium/glucose cotransporter 1, SLC5A1; GLUT2, glucose transporter 2, SLC2A2; DRA, downregulated in adenoma, SLC26A3; PAT1, putative anion transporter 1, SLC26A6; CFTR, cystic fibrosis transmembrane conductance regulator, Kir7.1, potassium inwardly rectifying channel, subfamily J, member 13, KCNJ13; ClC‐2, chloride channel protein 2, CLCN2. For detailed reviews about the physiology and pathophysiology of intestinal electrolyte transport and Na+/H+ exchange in particular, see Fuster and Alexander (), He and Yun (), Zachos et al. (), and Gurney et al. ()
Figure 4. Figure 4. Colonic epithelial Na+/H+ exchange in relation to other electrolyte fluxes and short‐chain fatty acid absorption and metabolism. NHE1, NHE2, NHE3, and NHE8, Na+/H+ exchangers; SLC9A, SLC9A2, SLC9A3, and SLC9A8, respectively; DRA, downregulated in adenoma, SLC26A3; CFTR, cystic fibrosis transmembrane conductance regulator; AE1, anion exchanger 1, SLC4A4; MCT1, monocarboxylate transporter 1, SLC16A1. Apical SCFA/Cl exchange indicated with question mark depicts described transport modality without identified transport protein/gene responsible. SCFA‐H, protonated short‐chain fatty acids; SCFA‐, ionized forms of short‐chain fatty acids. For additional sources, the reader is referred to reviews listed in Figure 3, and Binder () and Kunzelmann and Mall ().


Figure 1. Simplified model of basolateral and apical electrolyte transport in the (A) acinar and (B) ductal cells of the salivary (parotid) gland. NKCC1, Na‐K‐Cl cotransporter, SLC12A2; NHE1‐4, Na+/H+ exchangers 1 to 4, SLC9A1‐A4; AE2, anion exchanger 2, SLC4A2; CFTR, cystic fibrosis transmembrane conductance regulator; AQP1, aquaporin 1; AQP5, aquaporin 5; NBCe1‐B, major splice variant of the electrogenic Na+/HCO3 cotransporter (NBCe1, SLC4A4); NBCn1, electroneutral sodium/bicarbonate cotransporter, SLC4A7; ENac, electrogenic Na+ channels, SCNN1; KCa1.1 and KCa3.1, calcium‐activated potassium channels, KCNMA1 and KCNN4, respectively. For detailed reviews of the key players and mechanism involved, see Ohana () and Roussa et al. (). Question marks indicate controversial contribution of individual transport proteins.


Figure 2. Simplified model of basolateral and apical electrolyte transport in the (A) acinar and (B) ductal cells of the exocrine pancreas. NHE1, NHE4, Na+/H+ exchangers 1 and 4; SLC9A1 and SLC9A4, respectively; pNBC1, electrogenic Na+/HCO3 cotransporter, SLC4A4, AE2, anion exchanger 2, SLC4A2; CFTR, cystic fibrosis transmembrane conductance regulator; SLC26A6 (apical Cl/HCO3 exchanger). For detailed review of the key players and mechanism involved, see excellent reviews by Steward and Ishiguro (), Steward et al. (), and Ishiguro et al. ()


Figure 3. Simplified cellular model of the role of apical Na+/H+ exchange in transepithelial sodium, glucose, and water absorption in small intestinal epithelial cells. SGLT1, sodium/glucose cotransporter 1, SLC5A1; GLUT2, glucose transporter 2, SLC2A2; DRA, downregulated in adenoma, SLC26A3; PAT1, putative anion transporter 1, SLC26A6; CFTR, cystic fibrosis transmembrane conductance regulator, Kir7.1, potassium inwardly rectifying channel, subfamily J, member 13, KCNJ13; ClC‐2, chloride channel protein 2, CLCN2. For detailed reviews about the physiology and pathophysiology of intestinal electrolyte transport and Na+/H+ exchange in particular, see Fuster and Alexander (), He and Yun (), Zachos et al. (), and Gurney et al. ()


Figure 4. Colonic epithelial Na+/H+ exchange in relation to other electrolyte fluxes and short‐chain fatty acid absorption and metabolism. NHE1, NHE2, NHE3, and NHE8, Na+/H+ exchangers; SLC9A, SLC9A2, SLC9A3, and SLC9A8, respectively; DRA, downregulated in adenoma, SLC26A3; CFTR, cystic fibrosis transmembrane conductance regulator; AE1, anion exchanger 1, SLC4A4; MCT1, monocarboxylate transporter 1, SLC16A1. Apical SCFA/Cl exchange indicated with question mark depicts described transport modality without identified transport protein/gene responsible. SCFA‐H, protonated short‐chain fatty acids; SCFA‐, ionized forms of short‐chain fatty acids. For additional sources, the reader is referred to reviews listed in Figure 3, and Binder () and Kunzelmann and Mall ().
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Further Reading

Comprehensive reviews on mammalian Na+/H+ exchange were published by Orlowski & Grinstein (220, 221), by Zachos et al. (336), Donowitz et al. (76), and by Gurney et al. (107) with a particular emphasis on intestinal Na+/H+ exchange.  Phylogenetic analysis of evolutionary relations among NHE sequences from all phyla,  including those sequences well characterized as well as  those electronically annotated based on sequence similarity, has been published by Brett, Donowitz and Rao (35).

Teaching Material

H. Xu, F. K. Ghishan, P. R. Kiela. SLC9 Gene Family: Function, Expression, and Regulation. Compr Physiol. 8: 2018, 555-583.

Didactic Synopsis

Major Teaching Points: Sodium is one of the five major elements in the human body. It is essential to maintain normal physiological function involving body-fluid volume, blood pressure, osmotic equilibrium, neuronal excitability, and nutrient transport, among others. The mechanisms of Na+ flux across biological membranes includes Na+/H+ exchange (NHE), a process crucial for Na+ absorption in the gastrointestinal tract and kidney. Defective NHE may contribute to the pathogenesis of acute and chronic diseases, such as hypotension or hypertension, diarrhea, or intestinal inflammation. In this review, we discuss the following:

  • Distribution and function of the SLC9 gene family members in the gastrointestinal tract.
  • Emphasize the roles of Na+/H+ exchange in intracellular pH regulation, gastric acid secretion, salivary and pancreatic secretion, hepatic physiology, epithelial sodium absorption, and mucosal protection in the gastrointestinal tract.
  • Transcriptional and posttranslational mechanisms of regulation of Na+/H+ exchangers during development, by physiological stimuli, and in pathophysiological conditions.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: This figure illustrates ion transporters expressed at the basolateral (interstitium or serosal side) and apical (luminal side) membrane of the acinar (A) and ductal (B) epithelial cells of the salivary gland. Acinar cells are primarily responsible for the fluid secretion. Inward-directed Na+ gradient created by the activity of Na+/K+ ATPase is utilized by other basolateral transporters, such as the electroneutral Na+/K+/2Cl cotransporter (NKCC1) to increase intracellular Cl levels with the aid of coupled basolateral Cl/HCO3 and Na+/H+ exchange. Increase in intracellular Cl concentration stimulates its exit along with HCO3 at the apical site via Cl channels. Activation of apical Cl channels coincides with activation of basolateral K+ channels (KCNN4 and KCNMA1), an event required to maintain the electrochemical driving force for Cl efflux. HCO3 fluxes require intracellular HCO3, which is provided by the activity of carbonic anhydrases (CA). During the catalysis of water, CA produce an intracellular acid load that has to be rapidly buffered via Na+/H+ exchange activity. The net transport of ions across the acinar cell creates an osmotic gradient, which drives water transport into the luminal space via the apical Aqp5 water channel with a contribution of paracellular route. During the second stage of secretion, ductal epithelial cells reabsorb NaCl to generate hypotonic saliva. Reabsorption of Na+ by the ductal cells is mediated by at least two Na+ uptake mechanisms: apical electroneutral Na+/H+ exchange and the amiloride-sensitive electrogenic Na+ channel (ENaC).

Figure 2. Teaching points: These two figures depict major transport proteins involved in the formation of pancreatic fluid in the acini (A) and pancreatic ducts (B). In humans, partly in response to stimulation by cAMP formation by the adenylyl cyclase-coupled hormone secretin, pancreas secretes approximately 2.5 L/day of a HCO3-rich fluid which acts both as a protective vehicle for the pancreatic enzymes and as a buffer in the duodenum. Acinar cells produce Cl-rich secretion primarily due to the activities of basolateral Na+/HCO3 cotransport and apical activity of CFTR, cystic fibrosis transmembrane conductance regulator. Basolateral Na+/H+ exchange, driven by the transmembrane Na+ gradient generated by Na+/K+-ATPase, raises pHi and promotes formation of HCO3 by hydration of CO2, catalyzed by carbonic anhydrase, and provides a mechanism for pHi regulation by extrusion of protons generated by carbonic anhydrase during water catalysis. Pancreatic juice is modified as it flows along the pancreatic ductal system via coordinated activities of a complex network of transporters, ultimately producing fluid with final concentrations of 140 mmol/L HCO3 and 20 mmol/L Cl.

Figure 3. Teaching points: This figure depicts the prominent role of apical Na+/H+ exchangers (NHE2, NHE3, and NHE8) and bicarbonate transporters (DRA and PAT1) in sodium and chloride absorption in the small intestine and its relationship with glucose transporter (SGLT1). Although NHE2/3/8 are all expressed at the apical membrane of the epithelial cells, their contribution to intestinal sodium absorption is not equal. NHE2 has little role in intestinal sodium absorption. NHE3 is the main player in sodium absorption after weanling, while NHE8 plays a more important role in sodium absorption during early life. By coupling with DRA, NHE3 function also provide a major pathway for electroneutral NaCl absorption. In addition, NHE3 activity is also enhanced by glucose flux via SGLT1, an apical sodium-dependent glucose transporter.

Figure 4. Teaching points: This figure depicts the prominent role of apical Na+/H+ exchangers (NHE2, NHE3, and NHE8) in colonic water and electrolyte absorption and its relationship with short-chain fatty acid absorption and metabolism. NHE2, NHE3, and NHE8 are depicted in together for illustrative purposes only. Although coexpressed at the apical membrane of absorptive surface epithelial cells, NHE2 is thought to play a more prominent role in this mechanism in colonic crypts, and NHE3 in the surface epithelial cells. NHE8 expression is more ubiquitous in colonic epithelial cells, including not depicted here goblet cells. NHE3 activity coupled with Cl/HCO3 exchange mediated by DRA is thought to provide major pathway for electroneutral NaCl absorption (mainly operational in the mid-section of the colon). In addition to transepithelial Na+ absorption and pHi regulation, Na+/H+ exchange may provide acidic milieu to facilitate dissociation of short-chain fatty acids (SCFA) to ionized forms transported via monocarboxylate transporter 1 (MCT1). In turn, intracellular acidification resulting from SCFA uptake stimulates apical Na+/H+ exchange, a mechanism believed to be responsible for proabsorptive and antidiarrheal effects of butyric acid.


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How to Cite

Hua Xu, Fayez K. Ghishan, Pawel R. Kiela. SLC9 Gene Family: Function, Expression, and Regulation. Compr Physiol 2018, 8: 555-583. doi: 10.1002/cphy.c170027