Regulation of electroneutral NaCl absorption by the small intestine

Abstract

Na(+) and Cl(-) movement across the intestinal epithelium occurs by several interconnected mechanisms: (a) nutrient-coupled Na(+) absorption, (b) electroneutral NaCl absorption, (c) electrogenic Cl(-) secretion by CFTR, and (d) electrogenic Na(+) absorption by ENaC. All these transport modes require a favorable electrochemical gradient maintained by the basolateral Na(+)/K(+)-ATPase, a Cl(-) channel, and K(+) channels. Electroneutral NaCl absorption is observed from the small intestine to the distal colon. This transport is mediated by apical Na(+)/H(+) (NHE2/3) and Cl(-)/HCO(3)(-) (Slc26a3/a6 and others) exchangers that provide the major route of NaCl absorption. Electroneutral NaCl absorption and Cl(-) secretion by CFTR are oppositely regulated by the autonomic nerve system, the immune system, and the endocrine system via PKAα, PKCα, cGKII, and/or SGK1. This integrated regulation requires the formation of macromolecular complexes, which are mediated by the NHERF family of scaffold proteins and involve internalization of NHE3. Through use of knockout mice and human mutations, a more detailed understanding of the integrated as well as subtle regulation of electroneutral NaCl absorption by the mammalian intestine has emerged.

Figure 1. Mechanism of electroneutral NaCl absorption by the intestinal epithelial cells

(A) Measurement of electroneutral NaCl absorption and cAMP-stimulated electrogenic Cl⁻ secretion. The basal (upper left) and cAMP stimulated (upper right) transepithelial movement of Na⁺ and Cl⁻ by rabbit illeal mucosa (1.12 cm² exposed area) were measured by the short-circuit technique (using Ussing chambers). Mucosal→serosal (absorption: abs.) and serosal→mucosal (secretion: sec.) movement are both shown. Net ion flux is shown in lower panel. In lower panel, positive values indicate net absorption, and negative value indicates net secretion. [Modified from Field (68)]. (B) Molecules involved in electroneutral NaCl absorption. Apical absorption of NaCl is mediated by Na⁺/H⁺ exchanger (NHE3) and anion exchangers (Slc26a3/6/9). Basolateral movelent of NaCl is mediated by Na⁺/K⁺-ATPase (NKA) and ClC-2 chloride channel. Metabolic CO₂ is the source of H⁺ and HCO₃ ⁻ ions via intracellular carbonic anhydrase II (CA) catalysis. Electrogenic Cl⁻ secretion is mediated by CFTR. (C) Direct or NHERF-mediated interaction between CFTR and transporters. Known interactive activation (+) and inhibition (−) are shown; “?” is unknown. R, R-region of CFTR; S, STAS domain of Slc26s.

Figure 2. Regulation of NHE3: endocrine, nervous, and immune

Absorptive (anti-secretory, red) and secretory (anti-absorptive, blue) signals are indicated. NE, norepinephrine or norepinephrinergic neuron; Ach, acetylcholine or cholinergic neuron; VIP, vasoactive intestinal peptide or VIPergic neuron; AII, angiotensin II; NPY, neuropeptide Y; 5-HT, 5-hydroxytryptamine or serotonin; SP, substance P; SST, somatostatin; EK, enkephalin; PYY, peptide YY; PGE2, prostaglandin E2; IFN-γ, interferon-γ; GC, glucocorticoid; GN, guanylin; UGN, uroguanylin; PKAα, cAMP-dependent protein kinase α; PKCα, protein kinase Cα; cGKII, cGMP-dependent protein kinase II; SGK1, serum and glucocorticoid-dependent protein kinase 1.