3. The parathyroid gland and calcium homeostasis Flashcards
Where are the parathyroids found?
Ar 4 poles of thyroid
ParaT made up of which cells?
Chief cells: Parathyroid hormone secretion
Oxyphilic cells: Of unknown function
Primary action of parathyroids?
Maintains plasma [ca2+]
Effect of the following on plasma [ca2+]:
- Parathyroid hormone + vit D3
- Calcitonin
Parathyroid hormone + vit D3
—> Increase in plasma Ca2+ conc
Calcitonin
—> Decrease in plasma Ca2+ conc
Where are the bodies calcium stores found?
99% in bone/teeth
Remaining 1% intracellular
Of the 0.1% Ca2+ in plasma…
i.e. 2.3-2.6mM
50% free
45% bound to protein
5% chelated do di-carboxylic acids e.g. citrate and lactate
Physiological functions of Ca2+?
- Prosthetic group for many enzymes and structural proteins (+/-calmodulin)
- Structure of the plasma membrane (essential for structure of Na+ channel and permeability of plasma membrane to Na+)
- Excitation-contraction coupling in muscle
- Excitation-secretion coupling at axonal terminals and in endocrine and exocrine glands
- Blood coagulation
- Major intracellular second messenger
Body calcium homeostasis?
At gut + ECF + bone + kidneys
At gut:
- Intake from diet
- Excretion in faeces
At ECF:
- Intake from diet + bone resorption + reabsorption from kidneys
- Loss in secretion into gut to become faeces + in bone formation + filtration at kidneys
At bone:
- Intake from formation from ECF Ca
- Loss by resorption into ECF
At kidneys:
- Intake from ECF filtration
- Loss by ECF reabsorption or in urine
Difference between body phosphate and calcium homeostasis?
Phosphate is also passed between ECF and soft tissues
There is a small phosphate store in ECF and bone
More Phosphate lost via urine
More Ca lost via faeces
More Phosphate absorbed from gut
PTH regulation
Chief cells have Ca2+ sensing receptors that bind to Ca2+
On binding to the metatrophic receptors there is activation of PLC- PIP2-DAG pathway.
-PIP2 activates IP3 which leads to Ca2+ release from SR.
-DAG activates PKC which influences PTH exocytosis from secretory granule
Both these processes INHIBIT PTH synthesis and release
So [Ca2+] increase inhibits PTH release
What is the process of PTH formation?
- Pre-proPTH structure of 115 residues. Made up of:
- Signal sequence
- Pro sequence
- Biologically active sequence
- C-terminal fragment sequence
2. Pro-PTH structure of 90 residues @ ER Made up of: -Pro sequence -Biologically active sequence -C-terminal fragment sequence
- PTH ready for secretion of 84 residues @ vesciles secretions. Made up of:
- Biologically active sequence
- C-terminal fragment sequence
Processing of Pro-calcitonin in the para-follicular ‘C’ cells within the thyroid or brain neurones
Pro-calcitonin is processing in two ways.
- In the Thyroid C cells by proteolytic processing to produce:
- N-terminal peptide
- Calcitonin
- CCP (Calcitonin C-terminal peptide) - In the brain cells by proteolytic processing to produce:
- N-terminal peptide
- CGRP (calcitonin gene-releated peptide)
- C-terminal peptide
CCP ?
CGRP?
CCP - calcitonin C-terminal peptide
CGRP - calcitonin gene- related peptide
What structures/cells make up cortical and trabecular bone?
Cortical bone structure at the centre
Trabecular bone: Lined by osteoblasts and OB precursors
Calcified bone matrix towards centre where the Haversian canal are found.
Osteocytes: Osteoblasts encased by calcified bone. Still have canaliculi connections. Mechanism of Ca movement to outer bone cells, key in remodelling
Bone formation and resorption, action of osteoblasts and osteoclasts
Trabecular bone has more remodelling vs cortical
On bone surface it is lined with osteoblasts, involved in porotein secretion (e.g. collagen forming bone portein) and osteo-calcin and asteo-nectin formation. Ca and phosphate also released and concentration from blood used for remodelling
Osteoclasts are larger and resorbing bone
Osteoclasts and blasts work together
PTH and VitD act on osteoblast cells, stimulate to release factors. Osteoblasts essentially release growth factors e.g. M-CSF which stimulates stem cells differentiation into osteoclast precursors. Vit D and M-CSF act together to produce mononuclear osteoclasts from the osteoclast precursors. Mononuclear osteoclasts fuse to form osteoclast (which are muclinuclear)
RANK ligand and IL-6 are cytokines that stimulate osteoclast activity, their release is stijmualtes by PTH and Vit D
Bone resorption process by osteoclasts?
Once formed they synthesise integrins from plasma membrane which bind to vitronectin to seal of an area of bone under the cell. This sealing allows the cell to control environment. By..
- Has v-type protein pump to allow it to pump acid which demineralises bone.
- Lysosomal enzymes are released
- Release of TRAP
Bone is reabsorbed. This process of stimulated by RANK ligand and IL-6 released from osteoblasts. Calcitonin inhibits bone resorption.
Forms of vit D
Vitamin D3:
Different isoforms
Vit D3 either from diet or synthesised from cholesterol bi-product in endogenous steroid synthesis.
Endogenous form called cholecalciferol
In liver this cholecalciferol undergoes 25 hydroxylation then….
In kidney Vit D is formed into it’s activate metabolite form due 1 hydroxylation process
Vit D3
Hydroxylated to become activate
Intestinal absorption of Ca2+
DIrect action with PTH in bone
VItamin D action in intestine, for Ca and Phosphate absorption.
1,25 dehydroxy VIt D binds to receptor in nucleus and interacts with Retinoid X receptor. These receptors are TFs, so found upstreams of genes. Protein synthesis in cytosol to produce proteins which are involved in Ca uptake channels across apical surface. Stimulates calbindin synthesis which is key for Ca absorption into interstitial space
Intestinal absorption of Phosphate
Apical surface has Sodium-phosphate co transporter whuich can take 2 Na’s for 1 HPO4. VItamin D encourages transcription of proteins involved in phosphate absorption in to the interstitial space. Also proteins involved in the Na-K-ATPase.
Feedback loops controlled plasma [Ca2+]?
Vit D responisble for Ca and phosphate uptake
Plasma Ca levels stimulate PTH release at low level and negatively inhibit PTH release at high levels
PTH is released into circulation and it’s main actions are in the kidney and the bone. In PTH in the bone there is bone resorption stimulated by binding to osteoblast binding. Leading to growth factors (cytokines e.g. RANK and IL-6) release to stimulate osteoclasts, leading to bone re-sorption. Ca and phosphate plasma levels increase
PTH actions in kidney
Ca reabsorbed in PCT mainly (65%). PTH binds to epithelial receptors and increases Ca reabsorption.
It also suppresses Phos reabsorption. This is bc you don’t want high levels of both minerals otherwise precipitation of Ca-Phos occurs.
PTH stimulates activation of Vit D in the kidney
Active VIt D stimulates Ca and Phos absorption in intestine and reabsorption of both in kidney.
PTH > Vit D
What stimulates calcium and phosphate reabsorption back into blood in kidney from tubule?
VITAMIN D
Same mechanisms as seen in the intestines
What is the active form of Vit D?
1,25 hydroxy Vit D
High plasma levels of Ca and phos drive….
Bone synthesis but Vit D is essential for their uptake remember.
PTH action in kidney?
Ca reabsorbed in PCT mainly (65%). PTH binds to epithelial receptors and increases Ca reabsorption.
It also suppresses Phos reabsorption. This is bc you don’t want high levels of both minerals otherwise precipitation of Ca-Phos occurs.
PTH stimulates activation of Vit D in the kidney
