Mechanisms of the Regulation of the IntestinalNa+/H+Exchanger NHE3

Abstract

A major of Na+ absorptive process in the proximal part of intestine and kidney is electroneutral exchange of Na+ and H+ by Na+/H+ 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 Na+/H+ exchanger regulation is based on heterologous expression of mammalian Na+/H+ exchangers in Na+/H+ 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.

Human intestinal epithelial cell line SK-CO15 is a new model system to study Na+/H+exchanger 3

“…We assessed the capacity of SK-CO15 cells as a model cell line for NHE3 regulation by examining the expression of NHERF proteins and regulation of NHE3 by selected agonists. NHERF1 and NHERF2 are two major regulatory proteins interacting with NHE3 and other signaling molecules (9,17). Indeed, SK-CO15 cells express both NHERF1 and NHERF2, although we did not determine the presence of NHERF3 (PDZK1) in these cells.…”

“…NHE3 activity is modulated by extrinsic factors via multiple mechanisms that include phosphorylation, trafficking, and interaction with regulatory proteins, which are often inter-dependent (9). We assessed the capacity of SK-CO15 cells as a model cell line for NHE3 regulation by examining the expression of NHERF proteins and regulation of NHE3 by selected agonists.…”

“…The plasma membranes of polarized epithelial cells are divided into apical and basolateral domains with asymmetric distribution of cytoplasmic organelles by vectorial sorting mechanisms (27). Na ϩ /H ϩ exchange is a major route of Na ϩ absorption in the small intestine and colon (9). Intestinal epithelial cells express multiple forms of Na ϩ /H ϩ exchangers (NHEs; Slc9a) among which the type 3, NHE3 (Slc9a3), is the primary brush-border NHE.…”

“…NHE regulating factor (NHERF) proteins play pivotal roles in the regulation of NHE3 (9,17). Of four NHERF isoforms characterized to date, NHERF1 is required for cAMP-dependent inhibition of NHE3 in the kidney although it is not obligatory in the intestine (23).…”

Gut hormones and gut microbiota: implications for kidney function and hypertension

“…For instance, glucocorticoids regulate sodium uptake via induction of expression of a number of sodium/proton antiporters, particularly (sodium/hydrogen exchanger) member 3 (SLC9A3) in ileum and proximal colon. 19,20 Likewise, via transcriptional upregulation and activation of SLC9A3 in the brush border membrane vesicles (BBMVs) of the proximal colon, aldosterone significantly increases sodium transport that is not observed when the BBMVs are derived from the ileum 21,22 (Figure 3). …”