Parathyroid hormone (PTH) serves a key role in calcium homeostasis.  The main function of PTH is to increase plasma calcium concentration.  PTH secretion is closely regulated by changes in plasma calcium concentration, which are detected by the human calcium-sensing receptor (hCaSR), a G protein–coupled receptor located on chief cells of the parathyroid gland.  hCaSR activation ultimately inhibits PTH release by inducing a second messenger cascade in which intracellular calcium levels rise due to the hydrolysis of the membrane phospholipid phosphatidylinositol bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG) by the membrane-bound enzyme phospholipase C (PLC).Secondary hyperparathyroidism (SHPT) is a condition characterized by excessive PTH release in response to depressed serum calcium or elevated serum phosphate levels.  The novel peptide AMG 416, an hCaSR agonist, is being investigated as a possible treatment for SHPT caused by end-stage renal disease (ESRD).  IP-1, a metabolite that acts downstream of IP3, is a marker of hCaSR activity.  Researchers used embryonic kidney cells lacking hCaSR (HEK-293T) and HEK-293T clone cells stably transfected with hCaSR (hCaSR) to measure IP-1 levels following AMG 416 treatment (Figure 1).Figure 1  IP-1 concentration in embryonic kidney cells lacking hCaSR (HEK-293T) and HEK-293T clone cells transfected with hCaSR (hCaSR) following AMG 416 treatmentThe dependence of AMG 416 on extracellular calcium was investigated by incubating hCaSR cells with increasing concentrations of AMG 416 in the presence or absence of calcium (Figure 2).Figure 2  IP-1 levels in hCaSR cells incubated with and without calcium and AMG 416 peptide (Note: IP-1 levels are normalized to the number of cells present in each culture.)In addition, the effect of AMG 416 on PTH concentration was measured in wild-type (WT) rats.  Blood samples were taken from male and female rats for 8 hours following administration of varying concentrations of AMG 416 (Figure 3), and PTH levels were measured.Figure 3  Serum PTH concentration following administration of AMG 416 to WT ratsAMG 416 (Velcalcetide) Activates the Calcium Sensing Receptor. Sarah Walter, Amos Baruch, Jin Dong, et al. Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 229-240 Question 39Which of the following is a potential complication of secondary hyperparathyroidism?A.Decreased bone mineralizationB.Decreased osteoclast activityC.Increased osteoblast activityD.Increased cortical bone massSubmit