The calcium-sensing receptor (CaSR)-specific allosteric modulator cinacalcet has revolutionized treatment of secondary hyperparathyroidism in patients with chronic kidney disease. However, its application is limited to patients with end-stage renal disease because of hypocalcemic side effects presumably caused by CaSR-mediated calcitonin secretion from thyroid parafollicular C-cells. These hypocalcemic side effects might be reduced by compounds that bias the signaling of CaSR leading to similar therapeutic effects as cinacalcet without stimulating calcitonin secretion. The present study used rat medullary thyroid carcinoma 6-23 cells as a model of thyroid parafollicular C-cells. Concentration-response experiments were conducted investigating the effects of two CaSR agonists (calcium and strontium) to activate different signaling entities. Interestingly, the potency of strontium-stimulated calcitonin secretion was elevated compared with calcium. The enhanced potency of strontium-mediated calcitonin secretion was caused by a different signaling pattern than that produced by calcium. The results suggest that calcitonin secretion can be affected by CaSR-stimulated signaling bias, which may be used to develop novel drugs for treatment of secondary hyperparathyroidism.
See article at J Pharmacol Exp Ther 2012, 343:638–649.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics