Regulation Of Calcium And Phosphate Flashcards
What are the normal limits of plasma calcium in the human body
2.20-2.60 mmol/L
- 40% is protein bound
- 50% is ionized clacium
10% is in the form of complexes with anions
Functions of extracellular and intracellular
Extracellular: (around 2.20-2.60 mmol/L)
- bone mineral
- blood coagulation
- membrane excitability
Intracellular: (usually within 10^-7M)
- neuronal activation
- hormone secretion
- muscle contraction
Calcium distribution in the body (NOT plasma)
67% = inorganic hydroxyapatite
28% = collagen
5% = noncollagenous proteins
99% is in the body’s skeleton at anytime!!
What are the three major organ systems that are responsible for calcium homeostasis
Bones
- PTH increases resorption
Kidneys
- PTH increases reabsorption
GI
- active vitamin D increases absorption
PTH direct responses in kidney ,GI and bone
Bones
- PTH stimulates osteoclasts to erode matrix and release stored calcium
- works synergistically with 1,25
Kidneys
- increases release of calcitriol which stimulates calcium reabsoption in kidneys and decreases phosphate reabsorption
- does both by stimulating Gs and Gi protein coupled receptors on PCT cells
Intestines
- acts indirectly on intestines by increasing 1,25 and calcitriol levels which work to enhanced and calcium absorption is increased
**all three increase calcium levels in blood
What receptors are on Chief cells in thyroid to release PTH?
Decreased in plasma calcium concentration is sensed by calcium sensing G-protein-coupled receptor (CaSR) on chief cells
The chief cells release PTH in response to activation of these receptors
What is the PTH receptor?
Gs protein coupled receptor
- upregulates cAMP, AC and eventually PKA
PTH gene expression
Upregulation of CaSR receptors on chief cells blocks expression of PTH gene (CaSR is a Gq-GI coupled receptor)
CaSR receptor activation upregulates PTH mRNA production which goes through multiple steps to become mature PTH in vesicles
- CaSR activation also overtime induces a negative regulation on CaSR downstream signaling
active vitamin D also plays a small role in this as well but instead upregulates CaSR gene expression which makes more CaSR receptors on chief cell surface
Active PTH = 84aa and half life = 5 minute
Inactive PTH = 34aa and half life = 30 seconds
PTH-related protein (PTHrP)
It is a peptide paracrine hormone produced by severe allergic adults tissues (skin, hair, breast, etc)
- bind to similar receptors to PTH but does have its own receptors part that it recognizes
- although it is similar in structure to PTH, PTH and PTHrP have their own unique genes**
Function
- regulates proliferation and differentiation
- relaxes smooth muscles in response to stretch of blood vessels/uterus/bladder
- during lactation also promotes maternal bone resorption and transport of calcium into milk
- regulates calcium transport across the placenta and helps regulate chondrocyte proliferation in growth plate of long bones
is not regulated by circulating calcium and does not play a role in Ca/Pi homeostasis
is associated with hypercalcemia of malignancy (especially lung and thyroid) where certain tumors secrete high levels of PTHrP and produces symptoms similar to hypercalcemia
Osteoblasts vs osteoclasts
Both arise from mesenchymal stem cells with produces osteoblasts
- osteoblasts then turn into osteocytes within mature bone and on signal multiple osteocytes can form into osteoclasts
- osteocytes can also turn back into osteoblasts via PTH binding
Osteoblasts turn into osteoclasts via M-CSF and RANKL binding
- OPG blocks this interactions of RANKL and RANK
PTH function on kidneys
PTH binds to Gs protein coupled receptors
And upregulates cAMP/AC/PKA which in the end inhibits NA+/Pi cotransport
- results in decreased phosphate reabsorption and phosphaturia (increased phosphate excretion)
Mechanism of calcium absorption in intestinal epithelial cells
1) calcium diffuses from lumen into cell down its electrochemical gradient
2) calcium becomes bound inside the cell to calbindin (D-28K)
3) calbindin bound to calcium is pumped across the basolateral membrane into the blood via Ca2/ATPase pumps
1,25-Dihydroxycholecalciferol induces synthesis of calbindin D-28K and ATP inside intestinal cells
Main effects of calcitonin
Antagonizes PTH secretion and actions based on increased plasma calcium levels
- triggered when calcium goes above 11mg/dL
Bones = inhibits osteoclast activity and promotes calcium deposition in bones
Kidney = inhibits calcitriol release and calcium reabsorption
Intestines = calcium absorption is decreased by limiting calmodulin (D-28K) production
calcitonin however does NOT play a major function in regulating serum calcium but rather antagonizes PTH
How does rickets/osteomalacia occur?
Deficiency in active vitamin D (1,25-OH) causes a decrease in intestinal absorption of calcium.
This results in an excess of PTH in an attempt to raise calcium levels to normal.
- however PTH also inhibits Pi reabsorption in the kidney which incidentally results in hypophosphatemia (THIS IS WHAT CASUES RICKETTS/OSTEOMALACIA)
Decrease phosphate results in less hydroxyapatite band weakened bones
Symptoms:
- bowed legs and knob-like rib heads as well as short stature in ricketts
- bone pain and muscle weakness in osteomalacia
Primary and secondary causes of hyperparathyroidism
Primary = within the hyperthyroid glands themselves
- carcinoma, adenoma or hyperplasia
Secondary = renal failure, vitamin D deficiency
Tertiary = parathyroid syndrome from ectopic cancer (almost always small cell lung cancer
