Passage
Parathyroid hormone (PTH) is an important regulator of calcium and phosphate homeostasis. Specifically, PTH functions to increase plasma calcium concentration and reduce plasma phosphate levels. 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 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 secondary hyperparathyroidism caused by end-stage renal disease (ESRD) . IP-1, a downstream metabolite 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 treatment (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, PTH concentration was measured in 5/6 Nx mice, an animal model of secondary hyperparathyroidism in human ESRD. Blood samples were taken from male and female 5/6 Nx mice 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 5/6 Nx mice
-Assume that 5/6 Nx mice have a normal physiological response to changes in PTH secretion, and that AMG 416 treatment suppresses PTH release. Which graphic represents the blood phosphate levels that would be expected in 5/6 Nx mice eight hours after injection with indicated dosages of AMG 416?

Question

Passage
Parathyroid hormone (PTH) is an important regulator of calcium and phosphate homeostasis. Specifically, PTH functions to increase plasma calcium concentration and reduce plasma phosphate levels. 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 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 secondary hyperparathyroidism caused by end-stage renal disease (ESRD) . IP-1, a downstream metabolite 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 treatment (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, PTH concentration was measured in 5/6 Nx mice, an animal model of secondary hyperparathyroidism in human ESRD. Blood samples were taken from male and female 5/6 Nx mice 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 5/6 Nx mice
-Assume that 5/6 Nx mice have a normal physiological response to changes in PTH secretion, and that AMG 416 treatment suppresses PTH release. Which graphic represents the blood phosphate levels that would be expected in 5/6 Nx mice eight hours after injection with indicated dosages of AMG 416?

Quizplus · Accepted Answer

11ecba2d_0fbb_2416_a3bf_a59d1efcfb9c_MD0008_00 According to the passage, the 5/6 Nx mouse is an animal model of secondary hyperparathyroidism in human ESRD. This means that 5/6 Nx mice exhibit low plasma calcium, causing PTH to increase in an attempt to correct this imbalance. The passage mentions that AMG 416 is an hCaSR agonist, meaning that AMG 416 is able to bind the hCaSR receptor in the parathyroid gland and induce a similar biological response as that of normal ligand binding. The question states that AMG 416 treatment suppresses PTH release. Therefore, AMG 416 binding to hCaSR will suppress the increased PTH release seen in secondary hyperparathyroidism. Figure 3 shows that as AMG 416 dosage increases, PTH levels decrease. This graph depicts PTH concentration immediately and at four time points following administration of three different AMG 416 dosages to 5/6 Nx mice. PTH levels return to the 100% baseline eight hours after 0.3 mg/kg AMG 416 administration. However, treatment with higher AMG 416 dosages of 1 mg/kg and 3 mg/kg result in suppressed PTH levels at 50% and 25% of the baseline, respectively. PTH is most suppressed at the highest AMG 416 dosage of 3 mg/kg after eight hours. The net result of PTH suppression will be decreased circulating calcium and increased phosphate (ie, the opposite of PTH release). Less PTH due to higher AMG dosages causes greater retention of serum phosphate. Therefore, as shown in the graph in Choice D, greater AMG 416 dosages correspond to increased serum phosphate concentrations (Choices A, B, and C). Educational objective: PTH release causes increased plasma calcium but decreases plasma phosphate. Decreased PTH availability or diminished physiological response to PTH will increase phosphate levels in the blood.

Passage Parathyroid Hormone (PTH) Is an Important Regulator of Calcium and and Phosphate