Lecture 8: Calcium and Phosphate Regulation

Question 1

What is the normal serum range of calcium?

Answer 1

2.2-2.6mM

Question 2

Why is calcium important?

Answer 2

1) membrane stability
2) neuronal transmission
3) bone structure
4) blood coagulation
5) muscle function
6) hormone secretion

Question 3

What is phosphate used for?

Answer 3

cellular energy metabolism (ATP)

Question 4

Hypoventiliation leads to ________________ which results in muscle weakness, renal dysfunction, hypoexcitability

Answer 4

hypercalcemia

Question 5

Hyperventilation leads to _______________ which results in hyperexcitability

Answer 5

hypocalcemia

Question 6

True or False: there is 10 fold more P than Ca in soft tissue

Answer 6

True

BUT there is more calcium in serum

Question 7

Calcium travels in the blood bound to what protein?

Answer 7

albumin (45% bound, 50% ionized)

therefore, albumin levels are a good indicator of free calcium availability

Question 8

What are the 3 regulators of calcium

Answer 8

1) Parathyroid (PTH)
2) Vitamin D (Calcitriol)
3) Calcitonin

Question 9

What contributes most to the rapidly exchangeable pool of calcium in the body?

Answer 9

constant turnover of bone

Question 10

What and where are parathyroid glands?

Answer 10

paired glands (4 total) at the posterior borders on lateral lobes of thyroid glands

Question 11

What 2 cells are found in parathyroid glands?

Answer 11

1) Chief/Principal —–> make PTH

2) Oxyphil —–> no known function

Question 12

What is the half life of the entire 84 amino acid PTH?

Answer 12

4 minutes!

Question 13

Which portion of the PTH molecule binds to the receptor?

Answer 13

N-terminal fragment

Question 14

What is PTHrP?

Answer 14

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

Question 15

What is the primary receptor of PTH?

Answer 15

PTH 1R (on osteoblasts and kidney)

• binds N terminal 1-34 fragment, 1-84, PTHrP

Question 16

What kind of receptor is PTH 1R?

Answer 16

GPCR

Question 17

What does PTH 2R do?

Answer 17

binds 1-34, not sure what else

Question 18

The net effect of PTH is to __________ plasma Ca++ and __________ plasma P

Answer 18

increase calcium

decrease phosphate

Question 19

Where is one of if not the largest PTH target?

Answer 19

bone (99% of Ca content is in bone)

Question 20

True or false: osteoclasts have PTH receptors

Answer 20

false – all effects of PTH on bone happen kind of indirectly

KEY: PTH stimulation of osteoclasts is INDIRECT

Question 21

What kind of cells make up most of the bone matrix?

Answer 21

osteocytes (terminally differentiated osteoblasts)

Question 22

What does PTH stimulate in osteoblasts?

Answer 22

macrophage colony stimulating factor (M-CSF)

Question 23

What does M-CSF do?

Answer 23

stimulates osteoclast production

Question 24

What is the RANK ligand?

Answer 24

agent that activates mature osteoclast (promotes multinucleation to actively reabsorb bone)

Question 25

What stimulates RANK ligand?

Answer 25

PTH

Question 26

What are the two important productions released into systemic circulation from bone degradation?

Answer 26

Ca and P

Question 27

What is the major antagonist of RANK ligand?

Answer 27

OPG (osteoprotegerin)

Question 28

What stimulates OPG?

Answer 28

estrogen (protects women from osteoporosis early on)

Question 29

What inhibits OPG?

Answer 29

cortisol (more bone resorption)

Question 30

What is the action of PTH on the kidney?

Answer 30

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)

Question 31

What is the primary regulator of PTH?

Answer 31

plasma calcium

Question 32

What senses plasma calcium?

Answer 32

CaSR (calcium sensing receptor) binds ionized Ca++ (inhibits PTH synthesis at promoter level and also stimulates degradation of preformed PTH)

Question 33

Where are CaSRs located?

Answer 33

chief cells, kidney tubules, C cell

Question 34

What role does vitamin D play in PTH regulation?

Answer 34

binds nuclear receptor VDH which inhibits PTH synthesis at promoter level also stimulates CaSR gene transcription (indirect effect on PTH)

Question 35

What is calciferol? Cholecalciferol? Calcidiol? Calcitriol? Ergocalciferol?

Answer 35

``` Calciferol: vitamin D Cholecalciferol: vitamin D3 Calcidiol: 25-D Calcitriol: ACTIVE Ergocalciferol: vitamin D2 (dietary from vegetables) ```

Question 36

What is vitamin d synthesized from?

Answer 36

cholesterol (steroid hormone)

Question 37

What is the active form of vitamin D?

Answer 37

1, 25- dihydroxycholecalciferol

Question 38

How does vitamin D travel in the blood?

Answer 38

Bound in plasma to vitamin D-binding protein

Question 39

Where is vitamin D made?

Answer 39

skin

Question 40

What are the vitamin D targets?

Answer 40

bone resorption gut absorption kidney reabsorption

Question 41

What effects does vitamin D have on bone?

Answer 41

directly mobilizes Ca++ from bone (osteoblasts and clasts have VDRs) indirectly promotes bone mineralization by increasing plasma Ca++

Question 42

What does vitamin D to in the intestine?

Answer 42

increases transcellular Ca++ absorption in duodenum (inhibits calbindin) stimulates Pi reabsorption from small intestine

Question 43

What are the 3 rapid responses of PTH?

Answer 43

1) increase CYP1a (which activates vitamin D) 2) increases bone turnover 3) increases Ca++ reabsorption and phosphate excretion by kidneys

Question 44

What is the slow response of PTH (also elicits negative feedback on PTH action)?

Answer 44

activation of vitamin D (1, 25 (OH)2)

Question 45

What is the one thing that vitamin D does that PTH does not?

Answer 45

increase dietary Ca++ absorption by small intestine

Question 46

What is the primary cause of hyperparathyroidism?

Answer 46

hyperplasia, carcinoma of parathyroid gland | hypercalcemia, kidney stones

Question 47

What is secondary hyperparathyroidism?

Answer 47

chronic renal failure (reduced vitamin D leads to excess PTH synthesis)

Question 48

What happens in hypoparathyroidism?

Answer 48

hypocalcemic tetany (reduced threshold for depolarization ---> MORE firing)

Question 49

What is the Chvostek sign?

Answer 49

twitching of facial muscles in response to tapping of facial nerve

Question 50

What is rickets? osteomalacia?

Answer 50

unmineralized bone due to vitamin D deficiency | decreased bone strength - bowing of long bones

Question 51

What is pseudohypoparathyroidism

Answer 51

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)

Question 52

Where is calcitonin produced?

Answer 52

C cells of thyroid gland

Question 53

True or false: thyroidectomy does not alter normal physiological range of Ca++

Answer 53

true (dont know what calcitonin does)

Question 54

What is the therapeutic use of calcitonin?

Answer 54

inhibits osteoclast reabsorption of and slows bone turnover (hypocalcemia)