Physiological studies in heterozygous calcium sensing receptor (CaSR) gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo

Abstract

Background: The calcium sensing receptor (CaSR) regulates serum calcium by suppressing secretion of parathyroid hormone; it also regulates renal tubular calcium excretion. Inactivating mutations of CaSR raise serum calcium and reduce urine calcium excretion. Thyroid C-cells (which make calcitonin) express CaSR and may, therefore, be regulated by it. Since calcium stimulates release of calcitonin, the higher blood calcium caused by inactivation of CaSR should increase serum calcitonin, unless CaSR mutations alter the responsiveness of calcitonin to calcium. To demonstrate regulatory effects of CaSR on calcitonin release, we studied calcitonin responsiveness to calcium in normal and CaSR heterozygous-ablated (Casr+/-) mice. Casr+/- mice have hypercalcemia and hypocalciuria, and live normal life spans. Each mouse received either 500 microl of normal saline or one of two doses of elemental calcium (500 micromol/kg or 5 mmol/kg) by intraperitoneal injection. Ionized calcium was measured at baseline and 10 minutes, and serum calcitonin was measured on the 10 minute sample.

Results: At baseline, Casr+/- mice had a higher blood calcium, and in response to the two doses of elemental calcium, had greater increments and peak levels of ionized calcium than their wild type littermates. Despite significantly higher ionized calcium levels, the calcitonin levels of Casr+/- mice were consistently lower than wild type at any ionized calcium level, indicating that the dose-response curve of calcitonin to increases in ionized calcium had been significantly blunted or shifted to the right in Casr+/- mice.

Conclusions: These results confirm that the CaSR is a physiological regulator of calcitonin; therefore, in response to increases in ionized calcium, the CaSR inhibits parathyroid hormone secretion and stimulates calcitonin secretion.

Figure 1

Blunted calcitonin responsiveness in Casr^+/- mice. On the left (1A), a logarithmic scatterplot of serum calcitonin versus ionized calcium level in wild type and Casr^+/- mice. The straight lines indicate the respective best-fit regression lines; the respective 95% confidence intervals for the fitted lines are also shown, and have been demarcated by double-headed arrows for easier recognition. On the right (1B), a normal plot of mean serum calcitonin (± SE) versus mean ionized calcium (± SE) in wild type and Casr^+/- mice. Vertical SE bars correspond to the calcitonin values, and horizontal error bars correspond to ionized calcium values. The peak calcitonin response of wild type and Casr^+/- was significantly different for both ionized calcium and calcitonin (p < 0.02). In both graphs, the closed squares indicate wild type values, and the open squares indicate Casr^+/- values.