Role of transporters in regulating mammalian intracellular inorganic phosphate

Abstract

This review summarizes the current understanding of the role of plasma membrane transporters in regulating intracellular inorganic phosphate ([Pi]_In) in mammals. Pi influx is mediated by SLC34 and SLC20 Na⁺-Pi cotransporters. In non-epithelial cells other than erythrocytes, Pi influx via SLC20 transporters PiT1 and/or PiT2 is balanced by efflux through XPR1 (xenotropic and polytropic retrovirus receptor 1). Two new pathways for mammalian Pi transport regulation have been described recently: 1) in the presence of adequate Pi, cells continuously internalize and degrade PiT1. Pi starvation causes recycling of PiT1 from early endosomes to the plasma membrane and thereby increases the capacity for Pi influx; and 2) binding of inositol pyrophosphate InsP8 to the SPX domain of XPR1 increases Pi efflux. InsP8 is degraded by a phosphatase that is strongly inhibited by Pi. Therefore, an increase in [Pi]_In decreases InsP8 degradation, increases InsP8 binding to SPX, and increases Pi efflux, completing a feedback loop for [Pi]_In homeostasis. Published data on [Pi]_In by magnetic resonance spectroscopy indicate that the steady state [Pi]_In of skeletal muscle, heart, and brain is normally in the range of 1-5 mM, but it is not yet known whether PiT1 recycling or XPR1 activation by InsP8 contributes to Pi homeostasis in these organs. Data on [Pi]_In in cultured cells are variable and suggest that some cells can regulate [Pi] better than others, following a change in [Pi]_Ex. More measurements of [Pi]_In, influx, and efflux are needed to determine how closely, and how rapidly, mammalian [Pi]_In is regulated during either hyper- or hypophosphatemia.

Keywords: SLC20; XPR1; inorganic phosphate; inositol pyrophosphates; regulation; transport.

FIGURE 1

(A) Metabolic processes resulting in intracellular Pi production, including nucleic acid synthesis, NTPases, NDPases, and phosphatases. (B) Processes utilizing Pi in mammalian cells, including glycolysis (GAPDH), oxidative phosphorylation, glycogen phosphorolysis, and the formation of matrix vesicles in mineralizing tissues. (C) Two recently described pathways for regulating plasma membrane Pi transport. 1) PiT1 is recycled to the plasma membrane during Pi depletion (Zechner et al., 2022). 2) Efflux mediated by XPR1 is stimulated by InsP8 (Wild et al., 2016) (Gu et al., 2017) (Wilson et al., 2013) (López-Sánchez et al., 2020) (Li et al., 2020). (D) Hypothetical time course of [Pi]_In, following a step increase in [Pi]_Ex, driven by InsP8 regulation of XPR1. The increase in [Pi]_Ex, by mass action, should decrease efflux through XPR1 and slightly increase PiT1/PiT2-mediated influx. The imbalance between influx and efflux should increase [Pi]_In. Increased [Pi]_In should inhibit the phosphatase activity of PPIP5K and increase [InsP8], which binds to the SPX domain of XPR1 and stimulates efflux, resulting in a decrease in [Pi]_In. Eventually, a new steady state should be reached with [Pi]_In higher than the previous state.