Novel strategies in drug discovery of the calcium-sensing receptor based on biased signaling
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Novel strategies in drug discovery of the calcium-sensing receptor based on biased signaling. / Thomsen, Alex Rojas Bie; Smajilovic, Sanela; Bräuner-Osborne, Hans.
I: Current Drug Targets, Bind 13, Nr. 10, 01.09.2012, s. 1324-35.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Novel strategies in drug discovery of the calcium-sensing receptor based on biased signaling
AU - Thomsen, Alex Rojas Bie
AU - Smajilovic, Sanela
AU - Bräuner-Osborne, Hans
PY - 2012/9/1
Y1 - 2012/9/1
N2 - 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.
AB - 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.
KW - Calcium
KW - Drug Discovery
KW - Humans
KW - Parathyroid Hormone
KW - Receptors, Calcium-Sensing
KW - Signal Transduction
U2 - 10.2174/138945012802429642
DO - 10.2174/138945012802429642
M3 - Journal article
C2 - 22702634
VL - 13
SP - 1324
EP - 1335
JO - Current Drug Targets
JF - Current Drug Targets
SN - 1389-4501
IS - 10
ER -
ID: 45253422