MOLECULAR PHYSIOLOGY OF INTESTINAL N⁺/H⁺ EXCHANGE

Abstract

The sodium/hydrogen exchange (NHE) gene family plays an integral role in neutral sodium absorption in the mammalian intestine. The NHE gene family is comprised of nine members that are categorized by cellular localization (i.e., plasma membrane or intracellular). In the gastrointestinal (GI) tract of multiple species, there are resident plasma membrane isoforms including NHE1 (basolateral) and NHE2 (apical), recycling isoforms (NHE3), as well as intracellular isoforms (NHE6, 7, 9). NHE3 recycles between the endosomal compartment and the apical plasma membrane and functions in both locations. NHE3 regulation occurs during normal digestive processes and is often inhibited in diarrheal diseases. The C terminus of NHE3 binds multiple regulatory proteins to form large protein complexes that are involved in regulation of NHE3 trafficking to and from the plasma membrane, turnover number, and protein phosphorylation. NHE1 and NHE2 are not regulated by trafficking. NHE1 interacts with multiple regulatory proteins that affect phosphorylation; however, whether NHE1 exists in large multi-protein complexes is unknown. Although intestinal and colonic sodium absorption appear to involve at least NHE2 and NHE3, future studies are necessary to more accurately define their relative contributions to sodium absorption during human digestion and in pathophysiological conditions.

Molecular cloning, tissue distribution and ontogenetic expression of sodium proton exchanger isoform 2 (NHE-2) mRNA in the small intestine of pigs

“…This indicated that NHE gene regulation may be species specific. However, no careful quantitation of the amount of NHE-2 protein along the horizontal intestinal axis has been reported (Zachos et al, 2005). The different distribution of transporters along the intestinal axis from proximal to distal may be due to the unique morphological characteristics of the intestine and substrates, even though further research is needed to confirm this.…”

“…cDNA encoding nine members of the family (NHE-1, NHE-2, NHE-3, NHE-4, NHE-5, NHE-6, NHE-7, NHE-8 and NHE-9) have been isolated and characterized in human and rodent (Wakabayashi et al, 1997;Zachos et al, 2005). The various NHE isoforms are known to be expressed in a tissue-specific manner, and presumably have different physiologic functions (Wakabayashi et al, 1997;Zachos et al, 2005). In the small intestine, three NHE isoforms (NHE-1, NHE-2 and NHE-3) have been identified.…”

“…Both NHE-2 and NHE-3 are involved in transepithelial Na 1 absorption in the mammalian gastrointestinal tract (Tse et al, 1992;Dudeja et al, 1996;Repishti et al, 2001). However, most previous studies focused on the molecular characteristics of specific gene and their functions in human and rodent (Orlowski et al, 1992;Tse et al, 1992;Wakabayashi et al, 1997;Repishti et al, 2001;Zachos et al, 2005). Information is not available for pig NHE-2 sequence and the developmental regulation of this gene involved in small intestinal mucosa secretion and maintaining intracellular pH process is not studied.…”

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…In the nephron, individual NHE isoforms have different functions. These functions are reflected in their differential expression along the segments of the nephron, their localization in renal epithelial cells at the basolateral (e.g., isoform NHE1) or apical surface (e.g., isoform NHE3), and their activation in response to distinct agonists [4][5][6][7][8][9][10][11][12][13].…”

Na+/H+ Exchangers in Renal Regulation of Acid-Base Balance

“…The putative structure of the mammalian protein with a 10-to 12-transmembrane N-terminus and a largely cytoplasmic C-terminus has been discussed in recent reviews. 9,10 Currently, the structure of the mammalian NHEs is really unknown. Although a low-resolution version of the prokaryotic protein is available, 11 the degree of sequence similarity does not permit homology modeling of the mammalian protein at present.…”