The role of calcium-sensing receptor signaling in regulating transepithelial calcium transport.

The calcium-sensing receptor (CaSR) plays a critical role in sensing extracellular calcium (Ca) and signaling to maintain Ca homeostasis. In the parathyroid, the CaSR regulates secretion of parathyroid hormone, which functions to increase extracellular Ca levels. The CaSR is also located in other organs imperative to Ca homeostasis including the kidney and intestine, where it modulates Ca reabsorption and absorption, respectively. In this review, we describe CaSR expression and its function in transepithelial Ca transport in the kidney and intestine. Activation of the CaSR leads to G protein dependent and independent signaling cascades. The known CaSR signal transduction pathways involved in modulating paracellular and transcellular epithelial Ca transport are discussed. Mutations in the CaSR cause a range of diseases that manifest in altered serum Ca levels. Gain-of-function mutations in the CaSR result in autosomal dominant hypocalcemia type 1, while loss-of-function mutations cause familial hypocalciuric hypercalcemia. Additionally, the putative serine protease, FAM111A, is discussed as a potential regulator of the CaSR because mutations in FAM111A cause Kenny Caffey syndrome type 2, gracile bone dysplasia, and osteocraniostenosis, diseases that are characterized by hypocalcemia, hypoparathyroidism, and bony abnormalities, i.e. share phenotypic features of autosomal dominant hypocalcemia. Recent work has helped to elucidate the effect of CaSR signaling cascades on downstream proteins involved in Ca transport across renal and intestinal epithelia; however, much remains to be discovered.