The calcium-sensing receptor regulates calcium absorption in MDCK cells by inhibition of PMCA

Abstract

Calcium transport across a monolayer of Madin-Darby canine kidney (MDCK) cells was measured in response to stimulation of the basal surface with calcium-sensing receptor (CaR) agonists. Stimulation of the CaR resulted in a time- and concentration-dependent inhibition of calcium transport but did not change transepithelial voltage or resistance. Inhibition of transport was not altered by pretreatment of cells with pertussis toxin but was blocked by the phospholipase C (PLC) inhibitor U-73122. To determine a potential mechanism by which the CaR could inhibit calcium transport, we measured activity of the plasma membrane calcium ATPase (PMCA). Stimulation of the CaR on the basal surface resulted in an inhibition of the PMCA in a concentration- and PLC-dependent manner. Thus stimulation of the CaR inhibits both calcium transport and PMCA activity through a PLC-dependent pathway. These studies provide the first direct evidence that calcium can inhibit its own transcellular absorption in a model of the distal tubule. In addition, they provide a potential mechanism for the CaR to inhibit calcium transport, inhibition of PMCA.

Influence of Calcium-Sensing Receptor Gene on Urinary Calcium Excretion in Stone-Forming Patients

“…The activation of CaSR by extracellular Ca inhibits tubular Ca reabsorption acting directly on ion transport (2,4). We propose that the 990Gly allele increases CaSR sensitivity or response to Ca ions.…”

“…A possible interpretation of these findings is that the decreased tubular Ca reabsorption, characterizing hypercalciuric patients, could overcome the enhancing effect of haplotype 2 on tubular Ca transport. In addition, the larger glomerular filtration of Ca, associated with increased Ca concentration in blood, could facilitate Ca loss in these patients (1,4). Conversely, in normocalciuric subjects carrying haplotype 2, the increase of filtered Ca could be balanced by the increased reabsorptive capacity.…”

“…It is activated by the increase of extracellular concentration of Ca ions, which bind to the large extracellular Nterminal domain of the CaSR molecule (1,2). CaSR exerts its cellular activity through the stimulation of a G protein by its intracellular tail (2), which leads to the inhibition of PTH production (3) and tubular Ca reabsorption (2,4). In addition, CaSR influences intestinal Ca absorption (5), bone remodeling (6,7), and even nervous transmission (8).…”

“…Studies in humans (9) and in canine tubular cells (4) showed an inhibitory effect of CaSR on cellular Ca transport, suggesting that CaSR plays a key-role in the regulation of Ca excretion. In keeping with these observations, CASR gene has been considered a candidate for idiopathic hypercalciuria (14), a familial disorder predisposing to Ca kidney stones and characterized by increased Ca excretion in the presence of normal Ca concentrations in plasma (15,16).…”

Calcium-sensing receptor gene polymorphisms in patients with calcium urolithiasis: a systematic review

“…The signaling pathway for this effect requires activation of Gq proteins. 30 In DCT the transepithelial PD is against Ca 2+ reabsorption and the paracellular permeability of Ca 2+ ions is very low. 31 Ca 2+ reabsorption is an active, transcellular process, which is regulated by PTH and 1,25(OH) 2 D 3 .…”