Lecture 8: Calcium and Phosphate Regulation Flashcards
What is the normal serum range of calcium?
2.2-2.6mM
Why is calcium important?
1) membrane stability
2) neuronal transmission
3) bone structure
4) blood coagulation
5) muscle function
6) hormone secretion
What is phosphate used for?
cellular energy metabolism (ATP)
Hypoventiliation leads to ________________ which results in muscle weakness, renal dysfunction, hypoexcitability
hypercalcemia
Hyperventilation leads to _______________ which results in hyperexcitability
hypocalcemia
True or False: there is 10 fold more P than Ca in soft tissue
True
BUT there is more calcium in serum
Calcium travels in the blood bound to what protein?
albumin (45% bound, 50% ionized)
therefore, albumin levels are a good indicator of free calcium availability
What are the 3 regulators of calcium
1) Parathyroid (PTH)
2) Vitamin D (Calcitriol)
3) Calcitonin
What contributes most to the rapidly exchangeable pool of calcium in the body?
constant turnover of bone
What and where are parathyroid glands?
paired glands (4 total) at the posterior borders on lateral lobes of thyroid glands
What 2 cells are found in parathyroid glands?
1) Chief/Principal —–> make PTH
2) Oxyphil —–> no known function
What is the half life of the entire 84 amino acid PTH?
4 minutes!
Which portion of the PTH molecule binds to the receptor?
N-terminal fragment
What is PTHrP?
parathyroid hormone related peptide
- mimics PTH in bone and kidney (normally at LOW conc, not regulator of plasma Ca)
- produced by tumors resulting in hypercalcemia
What is the primary receptor of PTH?
PTH 1R (on osteoblasts and kidney)
- binds N terminal 1-34 fragment, 1-84, PTHrP
What kind of receptor is PTH 1R?
GPCR
What does PTH 2R do?
binds 1-34, not sure what else
The net effect of PTH is to __________ plasma Ca++ and __________ plasma P
increase calcium
decrease phosphate
Where is one of if not the largest PTH target?
bone (99% of Ca content is in bone)
True or false: osteoclasts have PTH receptors
false – all effects of PTH on bone happen kind of indirectly
KEY: PTH stimulation of osteoclasts is INDIRECT
What kind of cells make up most of the bone matrix?
osteocytes (terminally differentiated osteoblasts)
What does PTH stimulate in osteoblasts?
macrophage colony stimulating factor (M-CSF)
What does M-CSF do?
stimulates osteoclast production
What is the RANK ligand?
agent that activates mature osteoclast (promotes multinucleation to actively reabsorb bone)
What stimulates RANK ligand?
PTH
What are the two important productions released into systemic circulation from bone degradation?
Ca and P
What is the major antagonist of RANK ligand?
OPG (osteoprotegerin)
What stimulates OPG?
estrogen (protects women from osteoporosis early on)
What inhibits OPG?
cortisol (more bone resorption)
What is the action of PTH on the kidney?
stimulates CYP1a - encodes 1a-hydroxylase which converts active form of vitamin D
stimulates Ca++ channel insertion in apical membrane of distal tubule (to reabsorb more)
What is the primary regulator of PTH?
plasma calcium
What senses plasma calcium?
CaSR (calcium sensing receptor)
binds ionized Ca++ (inhibits PTH synthesis at promoter level and also stimulates degradation of preformed PTH)
Where are CaSRs located?
chief cells, kidney tubules, C cell
What role does vitamin D play in PTH regulation?
binds nuclear receptor VDH which inhibits PTH synthesis at promoter level
also stimulates CaSR gene transcription (indirect effect on PTH)
What is calciferol? Cholecalciferol? Calcidiol? Calcitriol? Ergocalciferol?
Calciferol: vitamin D Cholecalciferol: vitamin D3 Calcidiol: 25-D Calcitriol: ACTIVE Ergocalciferol: vitamin D2 (dietary from vegetables)
What is vitamin d synthesized from?
cholesterol (steroid hormone)
What is the active form of vitamin D?
1, 25- dihydroxycholecalciferol
How does vitamin D travel in the blood?
Bound in plasma to vitamin D-binding protein
Where is vitamin D made?
skin
What are the vitamin D targets?
bone resorption
gut absorption
kidney reabsorption
What effects does vitamin D have on bone?
directly mobilizes Ca++ from bone (osteoblasts and clasts have VDRs)
indirectly promotes bone mineralization by increasing plasma Ca++
What does vitamin D to in the intestine?
increases transcellular Ca++ absorption in duodenum (inhibits calbindin)
stimulates Pi reabsorption from small intestine
What are the 3 rapid responses of PTH?
1) increase CYP1a (which activates vitamin D)
2) increases bone turnover
3) increases Ca++ reabsorption and phosphate excretion by kidneys
What is the slow response of PTH (also elicits negative feedback on PTH action)?
activation of vitamin D (1, 25 (OH)2)
What is the one thing that vitamin D does that PTH does not?
increase dietary Ca++ absorption by small intestine
What is the primary cause of hyperparathyroidism?
hyperplasia, carcinoma of parathyroid gland
hypercalcemia, kidney stones
What is secondary hyperparathyroidism?
chronic renal failure (reduced vitamin D leads to excess PTH synthesis)
What happens in hypoparathyroidism?
hypocalcemic tetany (reduced threshold for depolarization —> MORE firing)
What is the Chvostek sign?
twitching of facial muscles in response to tapping of facial nerve
What is rickets? osteomalacia?
unmineralized bone due to vitamin D deficiency
decreased bone strength - bowing of long bones
What is pseudohypoparathyroidism
congenital defect in G protein that associates with PTHR1 (PTH CANNOT BIND TO RECEPTOR)
resistance to PTH, TSH, LH, FSH (low calcium, high phosphate, elevated PTH, short stature)
Where is calcitonin produced?
C cells of thyroid gland
True or false: thyroidectomy does not alter normal physiological range of Ca++
true (dont know what calcitonin does)
What is the therapeutic use of calcitonin?
inhibits osteoclast reabsorption of and slows bone turnover (hypocalcemia)
