RT Journal Article
SR Electronic
T1 Strontium Is a Biased Agonist of the Calcium-Sensing Receptor in Rat Medullary Thyroid Carcinoma 6-23 Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 638
OP 649
DO 10.1124/jpet.112.197210
VO 343
IS 3
A1 Thomsen, Alex Rojas Bie
A1 Worm, Jesper
A1 Jacobsen, Stine Engesgaard
A1 Stahlhut, Martin
A1 Latta, Markus
A1 Bräuner-Osborne, Hans
YR 2012
UL http://jpet.aspetjournals.org/content/343/3/638.abstract
AB The calcium-sensing receptor (CaSR)-specific allosteric modulator cinacalcet has revolutionized the 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 dampened by compounds that bias the signaling of CaSR, causing similar therapeutic effects as cinacalcet without stimulating calcitonin secretion. Because biased signaling of CaSR is poorly understood, the objective of the present study was to investigate biased signaling of CaSR by using rat medullary thyroid carcinoma 6-23 cells as a model of thyroid parafollicular C-cells. By doing concentration-response experiments we focused on the ability of two well known CaSR agonists, calcium and strontium, to activate six different signaling entities: Gq/11 signaling, Gi/o signaling, Gs signaling, extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, intracellular calcium ([Ca2+]i) mobilization, and calcitonin secretion. The experiments showed that strontium biases CaSR signaling toward ERK1/2 signaling and possibly another pathway independent of Gq/11 signaling and [Ca2+]i mobilization. It is noteworthy that the potency of strontium-stimulated calcitonin secretion was elevated compared with calcium. Combining these results with experiments investigating signaling pathway components involved in calcitonin secretion, we found that the enhanced potency of strontium-mediated calcitonin secretion was caused by a different signaling pattern than that produced by calcium. Together, our results suggest that calcitonin secretion can be affected by CaSR-stimulated signaling bias, which may be used to develop novel drugs for the treatment of secondary hyperparathyroidism.