Molecular mechanisms in proximal tubular and small intestinal phosphate reabsorption (Plenary Lecture)

Renal and small intestinal (re-) absorption contribute to overall phosphate( P-i)- homeostasis. In both epithelia, apical sodium (Na+)/P-i-cotransport across the luminal (brush border) membrane is rate limiting and the target for physiological/pathophysiological alterations. Three different Na/P-i-cotransporters have been identified: (i) type I cotransporter(s)-present in the proximal tubule-also show anion channel function and may play a role in secretion of organic anions; in the brain, it may serve vesicular glutamate uptake functions; (ii) type II cotransporter(s) seem to serve rather specific epithelial functions; in the renal proximal tubule (type IIa) and in the small intestine (type IIb), isoform determines Na+-dependent transcellular P-i-movements; (iii) type III cotransporters are expressed in many different cells/tissues where they could serve housekeeping functions. In the small intestine, alterations in P-i-absorption and, thus, apical expression of IIb protein are mostly in response to longer term (days) situations (altered P-i-intake, levels of 1.25 (OH2) vitamin D-3, growth, etc), whereas in renal proximal tubule, in addition, hormonal effects (e.g. Parathyroid Hormone, PTH) acutely control (minutes/hours) the expression of the IIa cotransporter. The type II Na/P-i-cotransporters operate (as functional monomers) in a 3 Na+:1 P-i stoichiometry, including transfer of negatively charged (-1) empty carriers and electroneutral transfers of partially loaded carriers (1 Na+, slippage) and of the fully loaded carriers (3 Na+, 1 P-i). By a chimera (IIa/IIb) approach, and by site-directed mutagenesis (including cysteine-scanning), specific sequences have been identified contributing to either apical expression, PTH-induced membrane retrieval, Na+-interaction or specific pH-dependence of the IIa and IIb cotransporters. For the COOH-terminal tail of the IIa Na/P-i-cotransporter, several interacting PDZ-domain proteins have been identified which may contribute to either its apical expression (NaPi-Cap1) or to its subapical/lysosomal traffic (NaPi-Cap2).