PiT-2 coming out of the pits.

WHILE THE FUNCTIONS AND PURPOSES of a protein are invariant in biology, the view adopted by biologists often evolves with time sculpted by prevailing database and interpretations. PiT-2 along with its cousin PiT-1 (Na -coupled phosphate transporters of the SLC20 family) have been assigned varying roles and christened different aliases since their discovery. Although mammalian cells do not purposefully evolve mechanisms to host welcoming receptions for viral invaders, viruses exploit ubiquitous and abundant cell surface proteins to latch on to so they can replicate, exterminate, and perpetuate. As such targets, PiT-1 and PiT-2 were named “viral receptors” Glvr-1 and Ram-1, respectively (8), as traitors who betray the cell. When these proteins were found to mediate inorganic phosphate (Pi) transport into cells (7), they were renamed after their prokaryotic paralogs (hence PiT). All cells derive their phosphate essential for the synthesis of nucleotides, phospholipids, phosphoproteins, and phosphoglycans from extracellular sources. Because of their universal presence (hardly adequate justification), PiT-1 and -2 were assigned the appellation “housekeeping transporters”. The indispensible nature of “keeping house” notwithstanding, such nomenclature carries an overtone of basal constitutive roles for PiTs undeserving of the physiologists’ time and effort. This is reflected by the relative paucity of literature in phosphate physiology centered on PiT-1 and PiT-2 compared with the three luminary members NaPi-IIa, -b, and -c (SLC34A1, -2, and -3 and Npt2a, -b, and -c). A parallel is observed in the Na /H exchanger (NHE) field where cell biologists study the ubiquitous “housekeeping” NHE1 isoform intensely while it receives little interest from physiologists. In biomedical research, one is endowed with the pleasure and privilege of watching truth unfold. Revision and even abandonment of dear old models brings one closer to the truth. The first clone that jumpstarted phosphate physiology to its molecular age sustained Na -coupled phosphate transport in a heterologous system (NaPi-1, Npt1, SLC17) but is unlikely to execute that duty in vivo (2). Although NaPi-IIa was once felt to be the sole player (a direct result of being the sole cDNA) in proximal tubule physiology, NaPi-II2c is assuming an equally important role (12), although variance may exist between humans and rodent physiology. The article by Villa-Bellosta, Ravera, and coworkers (13) lays a seminal milestone in mammalian phosphate physiology by ushering PiT-2 into the spotlight of proximal tubule phosphate reabsorption. There are three crucial findings in this study. First is the localization of PiT-2 to the apical brush border made possible by the generation of an excellent polyclonal antiserum, thus unambiguously obliterating a previously held consensual notion (not fact) that PiTs are all basolaterally located (4). Second is the fact that switching from a lowto high-dietary phosphate suppresses NaPi-IIa and c-mediated transport by 32% and PiT2-mediated transport by 73%, proving Pit-2 to be a highly regulated protein. This functional finding was rendered possible by Ravera and coworkers’ (11) discovery of differential inhibitor sensitivity of NaPi-IIa and -c vs. PiTs. Third is that the three players of apical phosphate uptake (NaPi-IIa and c vs. PiT-2) adapt to changes in dietary phosphate via the common mechanism of protein redistribution but proceed via distinct tempo with PiT-2 assuming an intermediate time course between NaPi-IIa and NaPi-IIc. This paper definitively establishes at least three physiologically regulated apical phosphate transporters in the proximal tubule. The existence of multiple transporters in the proximal apical membrane for the same substrate is prototypic. Apical H extrusion utilizes the multisubunit H -ATPase and two NHE isoforms (1). Even simple glucose uptake involves at least two and perhaps more isoforms, and the ultimate panoply is epitomized by the colossal casts of genes devoted to the transport of amino acids, organic cations, and anions (9). The diverse array of transporters serves to ensure flexible substrate characteristics as well as multiple mechanisms and kinetics of transport regulation that are unlikely attainable by a single transporter. Axial changes in luminal potential difference and Na concentration are minimal, but changes in luminal pH and total phosphate concentrations ([Pi]) are large (Fig. 1). While the affinities for [Pi] of the three apical phosphate transporters are all in the submillimolar range, the pH sensitivities (via both substrate titration and direct gating) and uphill electrochemical concentrative capacities are extremely diverse (reviewed in detail in Ref. 14). The sensing of phosphate load and status as well as homeostatic control also has a hierarchy of response times that mandates diverse efferent mechanisms. Sensing in the intestinalportal-hepatic system is near instantaneous while excess or deple-