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 -