EXAM #1: CALCIUM METABOLISM Flashcards
Which cells of the parathyroid gland secrete PTH?
Chief cells of the parathyroid
Describe the synthesis of PTH.
1) Prepro-PTH in ribosomes
2) pro-PTH in ER
3) PTH in secretory granules of Golgi complex
What regulates the synthesis of PTH?
Ca++ and Vitamin D
How does Ca++ physiologically regulate PTH synthesis?
- CaR (Ca++ sensing GPCR) is present on chief cells of the parathyroid
- PLC pathway is activated by Ca++ binding leading to the synthesis of leukotrienes
- Leukotrienes cause PTH degradation
How does Vitamin D regulate PTH?
Vitamin D decreases the stability of PTH mRNA
What is the receptor for PTH signaling?
PTHR1 (GPRC) present on the surface of target cells
What are the two pathways for PTH signaling?
1) Adenylate Cyclase pathway using:
- cAMP
- PKA
2) PLC
- DAG
- IP3
- PKC
What determines the signaling pathway a cell utilizes?
NHERF1- Na+/H+ exchange regulatory factor
- Neg= AC
- Pos= PLC
What are the functions of PTH?
Net effect is to INCREASE serum Ca++ by:
1) Ca++ reabsoprtion in the kidney
2) Ca++ mobilization from bones
3) Intestinal absorption
How does PTH stimulate the reabsorption of Ca++ in the kidney?
Insertion and opening of a Ca++ channel
How does PTH effect Vitamin D in the kidney?
Increases the enzyme that makes active Vitamin D
Describe the effect of PTH binding to PTHR1 on osteoblasts.
1) PTH binds PTHR1 receptor on OSTEOBLASTS
2) RANKL (ligand) is synthesized by the osteoBLAST
3) RANKL binds RANK on the osteoCLAST
4) OsteoCLAST is activated to resorb bone
*Note that PTH also decreases the production of osteoprotegerin, a molecule that prevents RANKL and RANK binding
What are the major electrolyte changes that occur in response to hyperparathyroidism?
1) Hypercalcemia
2) Hypercalciuria
3) Decreased plasma phosphate
Why does chronic renal failure lead to hyperparathyroidism?
1) Decreased Vitamin D
2) NO negative feedback on parathyroid
3) PTH increases
What is the most common cause of hypoparathyroidism?
Surgical removal of the parathyroid glands
What is the major effect on Ca++ in hypothyroidism?
Hypocalcemia
What is the difference between Vitamin D2 and Vitamin D3?
1) Ergocalciferol (D2)= plant
2) Cholecalciferol (D3)= human
How is Vitamin D3 synthesized?
1) UV light causes formation of provitamin D3 from a cholesterol precursor
2) Provitamin D3 is isomerized to Vitamin D3 (cholecalciferol) and is transported to the liver
3) Cholecalciferol in the liver is hydroxylated to 25-OH Vitamin D3
4) A second hydroxylation occurs in the kidney, forming the active form of Vitamin Dā1,25 OH Vitamin D3 (Calcitriol)
*1a-hydroxylase is key in kidney
How is Vitamin D3 transported in the circulation to the liver?
Bound to Vitamin D Binding Protein (DBP)
What is the effect of high serum Ca++ on Vitamin D?
Ca++ inhibits hydroxylation 25-OH Vitamin D3
What is the effect of PTH on Vitamin D?
- PTH increases 1-a hydroxylase activity in the kidney
- Thus, 1,25-OH Vitamin D3 is increased (Calcitriol)
How does Calcitriol (Vitamin D) effect Ca++ absorption in the gut?
Increases Ca++ absorption
What transported mediates the uptake of Ca++ from the gut?
TRPV6
What mediates Ca++ exit from the gut on the basolateral side of the epithelium?
1) PMCA
2) Na+/Ca++ exchanged (NCX)
What is the effect of Calcitriol on the kidneys?
Increased renal Ca++ reabsorption
How does Calcitriol stimulate renal Ca++ reabsorption?
1) Activation of Ca++ ATPase
2) Calbindin-D28K
What is the effect of Calcitriol on bone?
Stimulation of bone resorption, mobilizing Ca++
What can excess Vitamin D result in?
- Calcinosis (i.e. calcification of soft tissues)
- Deposition of Ca++ in kidney (stones)
- Hypercalcemia
What major bone disorders are caused by Vitamin D deficiency?
Rickets and osteomalacia
Where is Calcitonin synthesized?
Parafollicular C cells of the thyroid
What does increased Ca++ do to Calcitonin?
Increased synthesis of Calcitonin
What is the effect of Calcitonin in bone?
Inhibition of bone resorption
*****Opposite of PTH and Calcitriol
What is the effect of Calcitonin in the kidney?
Increases urinary Ca++ excretion
*****Opposite of PTH and Calcitriol
What is the effect of Calcitonin on serum Ca++?
Decreased serum Ca++
Clinically, how can Calcitonin be utilized?
Treatment of osteoporosis/ prevention of hypercalcemia in malignancy
*Note that high or low Calcitonin is not directly implicated in any disease state/disorder
What does Calcistat refer to?
Multiorgan calcium homestasis
