Regulation of Electroneutral NaCl Absorption by the Small Intestine

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⁻/HCO3⁻ (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.