Lecture 33 Flashcards
What function is calcium involved in?
- Enzyme activation/inactivation
- Intracellular second messenger
- Exocytosis
- Nerve conduction
- Muscle contraction
- Structural integrity of bone
How much calcium is taken up by each system that stores/takes up calcium?
- GI: +175mg/day (due to diet)
- Kidneys: -175mg/day (lost in urine)
- Bone: 0mg/day
How much calcium does bone hold?
Holds about 99% or 1 kg of calcium
What is the chemical name for calcitrol?
1,25-(OH)2-D
How does parathyroid hormone affect calcium?
- Acts directly on bone and kidney to increase calcium
- Through stimulation of calcitrol synthesis
- Inhibits renal tubular reabsorption of phosphate which increases urinary phosphate secretion and decreases plasma levels.
Where are parathyroid glands found?
On the posterior surface of the thyroid gland between capsule and surrounding connective tissue.
How many parathyroid glands are there?
4 major ones, may be a few accessory glands found in mediastinum or neck.
What do the 4 parathyroid glands derive from?
The third and fourth branchial pouches.
What does the third branchial pouch differentiate into?
- Inferior parathyroid glands
- Thymus
What does the fourth branchial pouch differentiate into?
- Superior parathyroid glands
- Ultimobranchial body
What are the two cell types within parathyroid glands?
Chief cells and oxyphil cells
What is the function of a chief cell?
Synthesize and secrete PTH
What is the function of an oxyphil cell?
Unclear, appears to be a transitional form of chief cells.
What are the unique characteristics of oxyphil cells?
- High amounts of mitochondria
- Acidophilic staining in hematoxylin-eosin preparations
- DOES NOT SECRETE PTH
What signals chief cells to secrete PTH secretion?
A calcium sensing receptor (CaSR) senses a reduction in serum calcium levels.
How does increased parathyroid hormone affect serum calcium concentrations.
Serum calcium is increased.
What is DiGeorge Syndrome (velo-cardio-facial syndrome)?
Absence of parathyroid glands and thymus which is caused by the deletion of a piece of chromosome 22 - “Catch-22”
How does DiGeorge Syndrome present?
Features vary but is associated with hypocalcemia and may include birth defects
How is the immune system affected by velo-cardio-facial syndrome?
Infections are common in children due to an absent/hypoplastic thymus, which leads to problems with T-cell-mediated response
What happens when calcium binds to CaSR?
The G-protein starts a signaling cascade that inhibits the PTH gene.
How does calcitrol affect chief cells?
- Directly inhibits PTH gene
- Activates CaSR gene (follows central dogma, with preCaSR being the term for the pre-post translational modified protein)
What happens when PTH gene is not inhibited?
PreproPTH is created from the gene, which then travels to the rough ER to be transformed into proPTH and then to PTH which is excreted via exocytosis.
Other than repressing the gene, how does calcium sensing affect PTH secretion?
The downstream signaling pathway that is activated by the G protein inhibits the secretion of PTH.
What is the signaling cascade that is caused by CaSR?
The G proteins inhibit adenylyl cyclase and stimulate phospholipase C (PLC) activity which results in suppression of PTH gene, accelration of intracellular degradation of PTH and inhibition of PTH release.
How does the activation of PLC affect the intracellular workings of the chief cells?
Production of the second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) from phosphoinostides (PIP2)
How does second messengers in chief cells inhibit release of PTH?
- IP3 increases levels of cytosolic calcium via the release of intracellular stores
- DAG stimulates protein kinase C (PKC) activity
- Elevated calcium and stimulated PKC inhibit release of granules containing PTH
Why does high cytoplasmic calcium contrast in its mechanism vs. other secretory cells?
It inhibits the fusion of vesiles with the membrane of the parathyroid cell, which inhibits PTH.
How do inactivating mutations of one allele of CaSR affect chief cells?
- Prevents increased serum calcium, leading to increased PTH
- Familial benign hypercalcemia (familial hypocalciuric hypercalcemia)
What are the effects of familial benign hypercalcemia?
- Severe if both alleles are inactivated
- Skeletal changes of unremitting hyperparathyroidsim
- Requires immediate parathyroidectomy in newborns
How do activating mutations of CaSR affect chief cells?
- Chief cells assume serum calcium is elevated when it is not, leading to decreased PTH
- Hypocalcemia
What are the effects of hypocalcemia?
Seizures can occur
How to treat hypocalcemia?
Treat with supplemental PTH
How can CaSR be affected by autoimmunity?
- Inactivated - syndrome similar to familial benign hypercalcemia
- Activated - hypoparathyroidism
How does PTH affect bone?
Promotes calcium and phosphate resorption from bone by acting on stromal osteoblasts in the bone marrow to demineralize and release calcium
How does PTH affect kidneys?
- Promotes calcium reabsorption in proximal tubules of the renal cortex and in the distal nephron
- Promotes phosphate excretion from the renal tubule.
- Stimulates biosynthesis of active calcitrol which increases calcium absorption in the intestinal mucosa
How does PTH affect the GI tract?
Promotes calcium absorption from the GI tract
What reaction in the skin account for the first step of vitamin D activation?
7-dehydrocholesterol reacts with sunlight to form vitamin D3.
What is plasma vitamin D made of?
Dietary vitamin D2/D3 and vitamin D3 from skin.
What does the liver do with plasma vitamin D?
It combines with 25-hydroxylase to create 25-OH D.
What do the kidneys do with 25-OH D?
It combines with 1-hydroxylase to create 1,25-(OH)2D (calcitrol)
What are the three proteins that directly account for intestinal absorption of calcium?
- Calcium-binding protein
- Calcium-stimulated ATPase
- Alkaline phosphatase
25-Hydroxycholecalciferol has what effect secondary effect on the process of vitamin D activation?
Inhibits the further production of 25-hydroxycholecalciferol (25-OH D) in the liver to prevent excessive action of vitamin D3.
Some calcium is secreted back into the small intestine
TRUE
Where does calcitonin come from and where does it end up?
It comes from the kidney and ends up in the bones.
What is released from bones to the extracellular fluid along with PTH?
- Calctriol
- Cortisol
Components of total serum calcium under normal condition:
- Albumin (4 Ca2+)
- Phosphorus citrate (1 Ca2+)
- Free Ca2+
- Normal levels of PTH
