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.

Keywords: Calcium-sensing receptor; FAM111A; calciotropic hormones; calcium homeostasis; calcium transport; intestine; kidney; signaling cascades.

Figure 1.

Schematic diagram of calcium (Ca²⁺) homeostasis. Increased plasma Ca²⁺ activates the calcium-sensing receptor (CaSR; protein structure represented in diagram in purple as a homodimer) in the parathyroid decreasing parathyroid hormone (PTH) release. Decreased PTH release, in addition to CaSR activation in the bone and kidney, results in decreased Ca²⁺ release from the bone and increased Ca²⁺ excretion in the urine. Decreased PTH indirectly causes decreased Ca²⁺ absorption from the small intestine by reducing the kidney production of 1,25-dihydroxyvitamin D (1,25(OH)₂VitD). CaSR activation in the small intestine also directly decreases Ca²⁺ absorption. Overall, increased plasma Ca²⁺ activates the CaSR in multiple organs decreasing PTH, as well as directly affecting Ca²⁺ transport in the kidney, bone, and intestine to lower plasma Ca²⁺ to a normal physiological range (1.1–1.25 mmol/L). (A color version of this figure is available in the online journal.)

Figure 2.

A schematic representation of calcium-sensing receptor (CaSR) signaling within epithelial cells. The CaSR has an extracellular domain (ECD) containing a Venus fly trap module (VFTM) and a cysteine rich region. It has seven transmembrane domains (TMD) and an intracellular domain (ICD). The CaSR forms homodimers by connection of the VFTMs via disulfide bonds. Calcium (Ca²⁺) binding within the VFTM activates the CaSR leading to signaling through G alpha (Gα) proteins (Gαq, Gαq11, Gαi, Gα12/13) and beta-arrestin (β-arrestin). Gαq11 stimulates phospholipase C (PLC)-mediated cleavage of phosphatidylinositol 4,5-bisphosphate (PIP₂) to diacylglycerol (DAG) and inositol 1,4,5, trisphosphate (IP3). IP3 induces release of Ca²⁺ from the endoplasmic reticulum (ER), thereby increasing cytosolic Ca²⁺ concentration ([Ca²⁺]_i). DAG activates protein kinase C (PKC) resulting in mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2) mediated gene transcription in the nucleus, and in the TAL specifically CLDN14. β-arrestin also stimulates MAPK and ERK1/2. Gαi inhibits adenylate cyclase (AC) and decreases cyclic adenosine monophosphate (cAMP). Gα12/13 activates PLD, which affects cytoskeletal reorganization. Gαq activation of Ras homolog family member A (RhoA) also stimulates cytoskeletal reorganization and gene transcription. (A color version of this figure is available in the online journal.)