Calcium Homeostasis II Flashcards
What is transcellular pathway of calcium absorption?
Calcium enters the apical membrane via calcium channels
Upon entering, calcium binds to calbindin-D9k
It is extruded across the basolateral membrane via a calcium ATPase - PMCA
How does Vitamin D3 affect calcium reabsorption in the small intestine?
Increases absorption via the transcellular pathway
How is phosphate absorbed in the intestine?
Paracellularly at tight junctions
Active transport involving a Na-phosphate cotransporter
Expression increased by Vitamin D3 and when dietary phosphate is low
How does PTH affect calcium resabsoprtion in the kidney?
Stimulates TRPV5 activity in the PCT and TAL
Also stimulates reabsorption in the DCT
How does PTH affect phosphate reabsorption in the kidney?
Increases urinary phosphate excretion by inhibiting reabsorption in the proximal and distal tubules
Promotes removal of sodium-dependent phosphate cotransporters from the luminal membrane
What is the affect of PTH on 1a-renal hydroxylase?
Induces its synthesis in the PCT
Catalizes the formation of active vitamin D (1,25(OH)2D3)
What is the active portion of PTH?
N-terminal region
Synthetic N-terminal fragments can induce all known actions of PTH
How do chief cells regulate the quantity of intact PTH getting released?
Utilize intraglandular degradation of stored hormone
Secretory vesicles contain proteases that degrade intact PTH to inactive C-terminal fragments
Describe the secretion of PTH in hypercalcemic and hypocalcemic states?
Hypercalcemic - decrease in secretion of intact PTH and an increase in release of inactive C-terminal fragments
Hypocalcemia - cheif cells release mostly intact PTH
What is the principal physiological regulator of PTH secretion?
Plasma concentration of ionic calcium
What is the response of chief cells to a decline in serum Ca?
Respond immediately to an acute decline in Ca by release preformed PTH
Decrease in intraglandular degradation of PTH, causing the release of more intact PTH
If prolonged, PTH gene transcription and an increased rate of chief cell proliferation occurs
How do chief cells respond to hypercalcemia?
Intraglandular PTH breakdown increases
However, PTH secretion is not totally suppressed due to the basal rate of PTH secretion
What is the calcium-sensing receptor (CaSR)?
G protein-coupled receptor that monitors minute-to-minute fluctuation in extracellular fluid Ca
What is the effect of 1,25(OH)2D3 on PTH secretion?
Active Vitamin D3 inhibits PTH secretion
What are the principal targets of PTH?
Kidneys and Bone
What is the type 1 PTH receptor?
Binds both PTH and PTH releated protein (PTHrP)
Increases intracellular cAMP levels
What is the affect of PTH on bone?
Mobilizes calcium from bone by promoting the expression of RANK-L
Also downregulates the expression of OPG
What are the affects of PTH on the kidneys?
Increase Ca reabsorption by acting on Tubule cells
Promotes phosphate excretion
Induces 1a-renal hydroxylase expression
What is the direct effect of PTH excess?
Bone lesions due to PTH-induced bone resorption
What are the effects of PTH-induced hypercalcemia?
Fatigue
Vomiting, ab pain, constipation, pancreatitis
Neuro symptoms
Impaired kidney function due to kidney stones
Decreased membrane excitability
What are the clinical features of PTH deficiency?
Tetany from the spontaneous discharge of the peripheral nerves
What is Pseudohypoparathyroidism?
Rare familial disorder characterized by target tissue resistance to PTH
What is the function of PTH related protein?
Activates the same receptor as PTH
But is produced locally and acts as a paracrine or autocrine regulator
Regulates calcium flux through the placenta
What is humoral hypercalcemia of malignancy?
Syndrome associated with malignant tumors
PTHrP is the most common mediator of HHM
What is Vitamin D3 and D2?
D3 - lipid soluble vitamin formed by a photolytic reaction
D2 - Formed from a platn sterol
Both are inactive until modification by kidney or liver enzymes
How is Vitamin D activated?
First step: conversion of vitamin D to 25 hydroxyvitamin D, this step is essentially unregulated
Second Step: Hydroxylation of 25(OH)D, this process is highly regulated and occurs in the PCTs of the kidneys
What is 25(OH)D?
Has very little activity
Long circulatory half-life and the most abundant form in the blood
This is what is measured when clincally assessing a patient’s Vitamin D status
How is the activation of Vitamin D regulated?
Hypocalcemia and increased PTH have stimulatory affects on 1a-hydroxylase activity
Increased calcium and low PTH decrease 1a-hydroxylase activity
Active Vitamin D also has a negative feedback effect on the enzyme
What is Vitamin D binding protein?
Principal carrier of vitamin D and vitamin D metabolites
What are the principal targets of active Vitamin D?
Small intestine
Bone
Parathyroid glands
What is the affect of active Vitamin D on the small intestine?
Enhances calcium absorption by inducing expression of epithelial calcium channels and calbindin-D9k
What is the most apparent consequence of vitamin D deficiency?
Decreased bone mineralization
What is the effect of active vitamin D on the parathyroid glands?
Negative feedback effect on PTH secretion by inhibiting the expression of the PTH gene
Induces the expression of the genes for the CaSR and the Vitamin D receptor
What is the effect of active vitmain D on bone?
Promotes mineralization by ensuring calcium and phosphate availability via its actions in the small intestine
Promotes osteoclastogenesis by inducting RANK-L expression
Suppresses OPG
What is the effect of active vitamin D on the kidney?
Modulates its own formation by inhibiting 1a-hydroxylase activity and stimulating 24-hydroxylase activity
What is the mechanism of action for Vitamin D?
Binds to Vitamin D receptor which acts as a ligand activated transcription factor
Forms a heterodimer with an unliganded retinoid X receptor (RXR)
The complex binds to a vitamin D response element in the regulatory region of a target gene
What results from vitamin D deficiency?
Rickets
Osteomalacia
What is calcitonin?
Polypeptide hormone secreted by parafollicular cells in the thyroid
Lowers plasma calcium levels by supressing bone resorption by osteoclasts
What stimulates the release of calcitonin?
High calcium levels
Gi hormones, particularly gastrin
