Evidence for a regulated Ca²⁺ entry in proximal tubular cells and its implication in calcium stone formation

Calcium phosphate (CaP) crystals, which begin to form in the early segments of the loop of Henle (LOH), are known to act as precursors for calcium stone formation. The proximal tubule (PT), which is just upstream of the LOH and is a major site for Ca²⁺ reabsorption, could be a regulator of such CaP crystal formation. However, PT Ca²⁺ reabsorption is mostly described as being paracellular. Here, we show the existence of a regulated transcellular Ca²⁺ entry pathway in luminal membrane PT cells induced by Ca²⁺-sensing receptor (CSR, also known as CASR)-mediated activation of transient receptor potential canonical 3 (TRPC3) channels. In support of this idea, we found that both CSR and TRPC3 are physically and functionally coupled at the luminal membrane of PT cells. More importantly, TRPC3-deficient mice presented with a deficiency in PT Ca²⁺ entry/transport, elevated urinary [Ca²⁺], microcalcifications in LOH and urine microcrystals formations. Taken together, these data suggest that a signaling complex comprising CSR and TRPC3 exists in the PT and can mediate transcellular Ca²⁺ transport, which could be critical in maintaining the PT luminal [Ca²⁺] to mitigate formation of the CaP crystals in LOH and subsequent formation of calcium stones.