Activation of the calcium-sensing receptor attenuates TRPV6-dependent intestinal calcium absorption

Whether the intestinal mucosal cells are capable of sensing calcium concentration in the lumen and pericellular interstitium remains enigmatic for decades. Most calcium-regulating organs, such as parathyroid gland, kidney and bone, are capable of using calcium-sensing receptor (CaSR) to detect plasma calcium and trigger appropriate feedback responses to maintain calcium homeostasis. Although both CaSR transcripts and proteins are abundantly expressed in the crypt and villous enterocytes of the small intestine as well as the surface epithelial cells of the large intestine, the studies of CaSR functions have been limited to amino acid sensing and regulation of epithelial fluid secretion. Interestingly, several lines of recent evidence have indicated that the enterocytes use CaSR to monitor luminal and extracellular calcium levels, thereby reducing the activity of transient receptor potential channel, subfamily V, member 6, and inducing paracrine and endocrine feedback responses to restrict calcium absorption. Recent investigations in zebra fish and rodents have also suggested the role of fibroblast growth factor (FGF)-23 as an endocrine and/or paracrine factor participating in the negative control of intestinal calcium transport. In this review article, besides the CaSR-modulated ion transport, we elaborate the possible roles of CaSR and FGF-23 as well as their crosstalk as parts of a negative feedback loop for counterbalancing the seemingly unopposed calciotropic effect of 1,25-dihydroxyvitamin D3 on the intestinal calcium absorption.

Download Full-text

Calcium-sensing receptor regulation of PTH-dependent calcium absorption by mouse cortical ascending limbs

AJP Renal Physiology ◽

10.1152/ajprenal.00346.2001 ◽

2002 ◽

Vol 283 (3) ◽

pp. F399-F406 ◽

Cited By ~ 66

Author(s):

Hiroki I. Motoyama ◽

Peter A. Friedman

Keyword(s):

Parathyroid Hormone ◽

Calcium Absorption ◽

Receptor Regulation ◽

Calcium Sensing Receptor ◽

Fura 2 ◽

Calcium Sensing ◽

Intracellular Ca ◽

Transepithelial Voltage ◽

Maximal Rise ◽

Cellular Ca

Resting Ca2+ absorption by cortical thick ascending limbs (CALs) is passive and proceeds through the paracellular pathway. In contrast, parathyroid hormone (PTH) stimulates active, transcellular Ca2+ absorption ( J Ca). The Ca2+-sensing receptor (CaSR) is expressed on serosal membranes of CALs. In the present study, we tested the hypothesis that activation of the CAL CaSR indirectly inhibits passive Ca2+ transport and directly suppresses PTH-induced cellular J Ca. To test this theory, we measured J Ca and Na absorption ( J Na) by single perfused mouse CALs. Net absorption was measured microfluorimetrically in samples collected from tubules perfused and bathed in symmetrical HEPES-buffered solutions or those in which luminal Na+ was reduced from 150 to 50 mM. We first confirmed that Gd3+ activated the CaSR by measuring intracellular Ca2+ concentration ([Ca2+]i) in CALs loaded with fura 2. On stepwise addition of Gd3+ to the bath, [Ca2+]i increased, with a half-maximal rise at 30 μM Gd3+. J Ca and transepithelial voltage ( V e,) were measured in symmetrical Na+-containing solutions. PTH increased J Ca by 100%, and 30 μM Gd3+inhibited this effect. V e was unchanged by either PTH or Gd3+. Similarly, NPS R-467, an organic CaSR agonist, inhibited PTH-stimulated J Ca without altering V e. Neither PTH nor Gd3+affected J Na. Addition of bumetanide to the luminal perfusate abolished J Na and V e. These results show that CaSR activation directly inhibited PTH-induced transcellular J Caand that cellular Ca2+ and Na+ transport can be dissociated. To test the effect of CaSR activation on passive paracellular Ca2+ transport, J Ca was measured under asymmetrical Na conditions, in which passive Ca2+ transport dominates transepithelial absorption. PTH stimulated J Ca by 24% and was suppressed by Gd3+. In this setting, Gd3+ reduced V e by 32%, indicating that CaSR activation inhibited both transcellular and paracellular Ca2+transport. We conclude that the CaSR regulates both active transcellular and passive paracellular Ca2+ reabsorption but has no effect on J Na by CALs.

Download Full-text

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

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.5.f815 ◽

2001 ◽

Vol 280 (5) ◽

pp. F815-F822 ◽

Cited By ~ 39

Author(s):

Kristy A. Blankenship ◽

J. Jason Williams ◽

Martha S. Lawrence ◽

Kenneth R. McLeish ◽

William L. Dean ◽

...

Keyword(s):

Calcium Transport ◽

Calcium Absorption ◽

Mdck Cells ◽

Distal Tubule ◽

Dependent Manner ◽

Potential Mechanism ◽

Calcium Sensing Receptor ◽

Basal Surface ◽

Calcium Sensing ◽

Stimulation Of

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.

Download Full-text