Calcium Homeostasis Flashcards
What bodily functions is calcium important for?
muscle contraction neurotransmitter release hormone secretion coagulation pathways enzymatic regulation
How does it circulate in the body?
50% ionised Ca2+
40% protein bound
10% complexed to anions
What cells produce PTH?
Chief cells of the parathyroid gland
How is it processed?
Pre-pro hormone cleaved once in the ER (25aa) and then again in the Golgi (6aa)
How does PTH achieve its effect on the kidney?
Acts via the PTHR (a GPCR) which activates transcription of the TRPV5 ion channel located on the apical membrane. Ca2+ flows in through this channel and binds to calbindin-D28. Calcium is exchanged into the blood via a Na/Ca exchanger.
How does PTH influence osteoclast activity?
It acts on osteoblasts to cause expression of RANKL. RANKL interacts with RANK on preosteoclasts which leads to demineralisation and breakdown of the bone matrix as they mature to osteoclasts.
How much of mammalian vitamin D requirements come from exposure to sunlight?
90-95%
What is the role of vitamin D binding protein (DBP)
Transports cholecalciferol to the liver.
What is Megalin?
A transmembrane protein that transports 25-hydrocholecalciferol to the kidney tubules.
How does Vitamin D have its affect?
It binds to the vitamin D receptor which acts as a TF in the prescence of vitamin D. This binds to response elements of the Calcium binding protein gene (CaBP)
What are the mechanisms of calcium absorption in the small intestine?
Active uptake via the Na/Ca exchanger (basolateral surface)
Transcellular transport
Endocytosis
n.b. all of these require a CaBP such as calbindin.
How does Vitamin D affect bone demineralisation?
Binds to VDR which induces RANKL expression.
Where is calcitonin synthesised and where does it have its effect?
Parafolicular C cells of the thyroid gland. Prevents bone resorption by its action on osteoclasts.
What suggests mammalian calcitonin is not as potent as that of lower vetebrates?
Patients with thyroid carcinomas do not have hypocalcaemia but salmon calcitonin administered to osteoporotic hypercalcaemic patients works.
Where is it likely thyroid glands have evolved from and why?
Gills. Fish do not have thyroids but express PTH and calcium sensing receptors (CaSR) in the gills.
What are the cell types in the PT gland and what are their functions?
Chief - secrete PTH
Clear - resting chief cells
Oxyphil - bigger than chief cells but no secretory granules. They form at puberty and are thought to increase with age.
What is the structure of the CaSR?
Large extracellular ligand-binding domain
Large intracellular COOH domain.
How does the CaSR work?
Ca binds to it and it is coupled to Gaq/11 which activates PLC leading to increased DAG and IP3. IP3 leads to rise in intracellular calcium which results in supression of PTH secretion. It also inhibits adenylate cyclase (and therefore PKA) and DAG increased PKC activity which also supress PTH secretion.
Which pharyngeal pouche(s) does man parathyroid gland arise from?
3&4 - common parathyroid/thymus primordium
What are the stages of PT development?
- Patterning of the 3rd pharyngeal pouch
- Specification of PT domain
- Migration towards thyroid lobes (E14)
- Differentiation of cells to PT cells.
What are the categories of molecules involved in PT development?
TFs
Secreted signalling molecules
What patterns of TF expression are needed for
a) initiation of the PT primordium
b) specification of the PT domain?
a) retinoic acid >hoxa3 >pax1&9>Eya1>Six1
b) shh>Tbx1>fgf8&Gcm2(+Bmp4)
