Regulation of intestinal electroneutral sodium absorption and the brush border Na+/H+ exchanger by intracellular calcium.
The intestinal electroneutral Na(+) absorptive processes account for most small intestinal Na(+) absorption in the period between meals and also for the great majority of the increase in ileal Na(+) absorption that occurs postprandially. In most diarrheal diseases, there is inhibition of neutral NaCl absorption. Elevated levels of intracellular calcium ([Ca(2+)](i)) are known to inhibit NaCl absorption and involve multiple components of the Ca(2+) signaling pathway. The BB Na(+)/H(+) exchanger NHE3 accounts for most of the recognized digestive changes in neutral NaCl absorption, as well as most of the changes in Na(+) absorption that occur in diarrheal diseases. Previous studies have examined several aspects of Ca(2+) regulation of NHE3 activity. These include phosphorylation, protein trafficking, and multiprotein complex formation. In addition, recent studies have demonstrated the role of the NHERF family of PDZ domain-containing proteins in Ca(2+) regulation of NHE3 activity, thereby adding a new level of complexity to understanding Ca(2+)-dependent inhibition of Na(+) absorption. In this article, we will review the current understanding of (1) Ca(2+) signaling events in intestinal epithelial cells; (2) Ca(2+) regulation of intestinal electroneutral sodium absorption, which includes NHE3; and (3) the role of the NHERF family of PDZ domain-containing proteins in Ca(2+) regulation of NHE3 activity. We will also present new data on using advanced imaging showing rapid BB NHE3 endocytosis in response to elevated [Ca(2+)](i).
Zachos
Nicholas C
NC
Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Kovbasnjuk
Olga
O
Donowitz
Mark
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism*; D008871:Microvilli / Q000378:metabolism; D054731:PDZ Domains; D010766:Phosphorylation; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
D017923:Sodium-Hydrogen Exchangers; D002118:Calcium