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

Abstract

The calcium-sensing receptor (CaSR) plays a critical role in sensing extracellular calcium (Ca2+) and signaling to maintain Ca2+ homeostasis. In the parathyroid, the CaSR regulates secretion of parathyroid hormone, which functions to increase extracellular Ca2+ levels. The CaSR is also located in other organs imperative to Ca2+ homeostasis including the kidney and intestine, where it modulates Ca2+ reabsorption and absorption, respectively. In this review, we describe CaSR expression and its function in transepithelial Ca2+ 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 Ca2+ transport are discussed. Mutations in the CaSR cause a range of diseases that manifest in altered serum Ca2+ 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 Ca2+ transport across renal and intestinal epithelia; however, much remains to be discovered.

Regulation of 1 and 24 hydroxylation of vitamin D metabolites in the proximal tubule

“…The CaSR also has effects outside of the parathyroid gland, with expression in organs such as the brain, kidney, and intestines where it has effects on neuropathological conditions and modulate renal calcium reabsorption and intestinal calcium absorption. 60,[96][97][98][99] It acts to modulate the expression and activity of calcium and phosphate transporters, channels and pores, including tight junction proteins that regulate both paracellular and transcellular calcium (re) absorption across renal and intestinal epitehlia. 59,97,[100][101][102] CaSR activity has also recently been linked to the modulation of CYP27B1 expression in a HEK-293 cell model.…”

“…57,58 Calcium ions bind to the extracellular domain of the CaSR, which at high levels activates the receptor, thereby suppressing PTH secretion when the blood calcium concentration is sufficiently high. 59,60…”

“…57,58 Calcium ions bind to the extracellular domain of the CaSR, which at high levels activates the receptor, thereby suppressing PTH secretion when the blood calcium concentration is sufficiently high. 59,60 Phosphate also affects CaSR signaling as a noncompetitive inhibitor, whereas calcium is an agonist to the receptor. 60 Elevated blood phosphate levels inhibit CaSR signaling, thus stimulating PTH secretion.…”

“…59,60 Phosphate also affects CaSR signaling as a noncompetitive inhibitor, whereas calcium is an agonist to the receptor. 60 Elevated blood phosphate levels inhibit CaSR signaling, thus stimulating PTH secretion. 61 In the kidney, PTH inhibits phosphate reabsorption from the proximal tubule and increases renal calcium reabsorption from the distal nephron.…”

Hereditary kidney diseases associated with hypomagnesemia

“…Hypomagnesemia in KCS type 2 patients could be attributed to degradation of transcription factors involved in magnesium homeostasis. Tan et al [90] suggested a potential role of FAM111A in regulation of CaSR, since KCS type 2 shares phenotypic characteristics with ADHH-like hypocalcemia and hypoparathyroidism.…”