Title:Novel Strategies in Drug Discovery of the Calcium-Sensing Receptor Based on Biased Signaling
Volume: 13
Issue: 10
Author(s): Alex Rojas Bie Thomsen, Sanela Smajilovic and Hans Brauner-Osborne
Affiliation:
Keywords:
Calcium-sensing receptor, parathyroid hormone, calcitonin, biased signaling, cinacalcet, signaling pathway, chronic kidney disease, PTH, CaSR, renal phosphate retention.
Abstract: A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention. Prolonged parathyroid
gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the
glands and excessive secretion of parathyroid hormone (PTH), which causes renal osteodystrophy. PTH secretion from
the parathyroid glands is controlled by the calcium-sensing receptor (CaSR) that senses extracellular calcium. High extracellular
calcium activates the CaSR causing inhibition of PTH secretion through multiple signaling pathways. Cinacalcet
is the first drug targeting the CaSR and can be used to effectively control and reduce PTH secretion in PTH-related
diseases. Cinacalcet is a positive allosteric modulator of the CaSR and affects PTH secretion from parathyroid glands by
shifting the calcium-PTH concentration-response curve to the left. One major disadvantage of cinacalcet is its hypocalcemic
side effect, which may be caused by increased CaSR-mediated calcitonin secretion from the thyroid gland. However,
multiple studies indicate that PTH and calcitonin secretion are stimulated by different signaling pathways, and therefore it
might be possible to develop a CaSR activating drug that selectively activates signaling pathways that inhibit PTH secretion
while having no effect on signaling pathways involved in calcitonin secretion. Such a drug would have the same
therapeutic value as cinacalcet in lowering PTH secretion while eliminating the side effect of hypocalcemia by virtue of it
not affecting calcitonin secretion. The present review will focus on recent advancements in understanding signaling and
biased signaling of the CaSR, and how that may be utilized to discover new and smarter drugs targeting the CaSR.
