The Need of a Paradigm Shift to Better Understand PiT1 and PiT2 Biology: Response to “Why Is There No PiT1/SLC20A1 Pathogenic Variants Yet Linked to Primary Familial Brain Calcification?”

Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8

“… 2 Thus, it may be of additional biological significance that PiT2 does not share the “moonlighting” activities of intracellular pools of PiT1 that are independent of its ability to transport Pi, including regulation of cell growth and differentiation, apoptosis, ER stress, immune responses, and glucose metabolism. 34 – 37 …”

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight

“…Unlike sodium phosphate co-transporters from the SLC34 family, PiT proteins are widely expressed, including in key organs involved in phosphate homeostasis regulation [ 57 ]. In bone, PiT1 and PiT2 are expressed in chondrocytes and osteoblasts [ 34 , 58 ] but the actual contribution of these proteins to bone mineralization is still a matter of debate [ 59 ]. Both PiT1 and PiT2 have been detected in the kidney, but localization at the apical membrane of the proximal tubule has only been confirmed for PiT2 [ 14 ].…”

“…Based on the relative expression levels of SLC20 proteins, the authors suggest that PiT1 rather than PiT2 is responsible for the low affinity phosphate absorption observed in rats with CKD [ 64 ]. In contrast, the widespread and low level expression of PiT2 in epithelial and non-epithelial cells throughout the intestine [ 64 ], together with its questionable role in transcellular phosphate absorption, indicates that this protein may potentially function as an intestinal phosphate sensor [ 59 ].…”