The Slc9a family of nine Na+/H+ exchangers (NHE) plays a critical role in neutral sodium absorption in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins mediate the electroneutral exchange of Na+ and H+ and are crucial in a variety of physiological processes, including the fine tuning of intracellular pH, cell volume control and systemic electrolyte, acid-base and fluid volume homeostasis. Here, we review the role of the Na+/H+ exchange mechanism as it relates to the physiology of organs and cells involved in nutrient absorption, and we describe physiological and molecular aspects of individual isoforms, including their structure, tissue-, and subcellular distribution, as well as their regulation by physiological stimuli at the transcriptional and post-transcriptional levels. A particular emphasis is placed on Na+/H+ exchanger isoforms expressed on the apical (brush border) membrane of the epithelial cells, and the consequences of gene-targeted mutation of individual isoforms are discussed in the context of the physiology of digestive organs. Where available, we also provide a review of pathophysiological states related to aberrant expression and/or activity of Na+/H+ exchangers within the confines of the digestive system.
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The proximal duodenal mucosa, exposed to frequent pulses of gastric acid, is functionally "leaky", increasing the importance of defense mechanisms such as the mucus gel layer, cellular acid/base transporters, bicarbonate secretion, and mucosal blood flow. Our laboratory has used a unique in vitro perfused microscopic system to measure thickness of the adherent mucus gel (MGT), intracellular pH (pHi), bicarbonate secretion, and mucosal blood flow in anesthetized rats. Exposure to pulses of luminal acid, mimicking the rapid physiologic shifts of luminal pH, increases MGT and blood flow, and induces cellular bicarbonate loading, the latter followed by augmented bicarbonate secretion. The mechanism by which the epithelium senses luminal acid includes capsazepine-inhibitable vanilloid receptors, presumably similar to the vanilloid receptor TPVR-1. CFTR, the cAMP-regulated anion channel mutated in the disease cystic fibrosis, plays an essential role in duodenal bicarbonate secretion. Our data are consistent with the hypothesis that cellular bicarbonate loading is an important means of preserving epithelial pHi during luminal acid challenge. Increased MGT may damp rapid shifts of luminal pH. Enhanced mucosal blood flow plays a significant role in the removal of back-diffusing acid. These neurally coordinated systems act coherently to defend the vulnerable duodenal epithelial cells from concentrated gastric acid.
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