Calcium Homeostasis (Week 4) Flashcards
what are the physiological functions of calcium
-skeletal rigidity - hydroxyapatite and calcium phosphate
-component of connective tissue and teeth
-haemostasis (blood clotting) intrinsic and extrinsic cascades
-excitation-contraction coupling - smooth and striated muscle
-stimulus - secretion coupling - acetylcholine from neuromuscular junction
- cell to cell adhesion - cadherins
second messenger for enzymatic activity - calmodulin
ionised meaning
free and biologically active
protein bound and non-diffusible
biologically inactive and not excreted
(dietary Ca2+) (Ca2+ reabsorbed from bones) =
(Ca2+ lost in faeces, sweat and saliva) (Ca2+ deposited in bone)
physiological function of inorganic phosphate (Pi)
formation of bone - calcium phosphate and hypoxyapatite crystals
formation of ATP
component of nucleotides, nucleosides and phospholipids
aids in cellular signalling through its role phosphorylating proteins and as a consituent of second messengers
what does inorganic phosphate normally exsist as
HPO4- or H2PO4-
plasma conc = 2.3mmol l-1
what are the 3 different hormones that achieve the homeostasis of calcium and act on the bones, kidneys and intestines
Metabolites of vitamin D (1,25-Dihydroxyvitamin D)
Parathyroid hormone (PTH)
Calcitonin
where is the parathyroid hormone manufactured
in chief cells of the parathyroid glands and is the most important of the three hormones, it responds to hypocalcaemia
what type of receptor is the calcium sensing receptor
g- protein coupled receptor
what is FHH
familial Hypocalciuric Hypercalcemia
what does it mean to have a heterozygous CaSR inactivating mutation in FHH
one normal CaSR gene and one mutated gene.
Mutated CaSR fails to do its Job of inhibiting parathyroid hormone secretion when the blood calcium levels get too high.
As a result PTH is not properly supressed when it should be
what does it mean to have mutations in heterozygous CaSR and Ga11
one normal CaSR gene and one mutated CaSR gene along with mutation in Ga11 .
when calcium levels are normal there is an abnormal response
means body gets rid of calcium in the urine
give a summary of the two types of calcium related mutations and how they affect the bodys abaility to regulate calcium
FHH: inability to suppress PTH when blood calcium is high
ADH: Excessive urinary excretion even when blood calcium level is normal
what are some roles mediated by CaSRs
Extracellular calcium homeostasis
nutrient sensor - parietal and G cells
Enzyme secretion - alpha cells and beta cells
what is Gq/11
it is a type of protein involved in cell signalling pathways
what is IP3 (Inositol triphosphate) and DAG( Diacylglycerol)
these are signalling molecules produces when CaSR is activated
when CaSR is stimulated, it triggers a signalling cascade that involves the production of IP3 and DAG
what does IP3 cause the release of
causes the release of calcium from intracellular stores into the cell, leading to an increase in intracellular calcium concentration.
what does DAG activate
protein kinase C
explain the process of IP3 and DAG
CaSR detects calcium levels
when activated it signals Gq/11, leading to the production of IP3 and DAG.
IP3 causes in increase in intracellular calcium
DAG activated PKC
where are parathyroid hormone receptors expressed
on osteoclasts in bone and in the proximal and distal tubule of the kidneys. Overall PTH is responsible for increasing extracellular Ca2+
bones 1
PTH stimulates cytokines that recruit osteoblasts
osteoblasts induce osteoclasts
GI tract 2
Activates synthesis of 1, 25 Dihydroxyvitamin D (kidney) increases transcellular uptake Ca2+ from the small intestine
Kidney 1
PTH increase Ca2+ reabsorption by increasing activity of Ca2+ channels and pumps
what is a prohormone
it is a precursor to a hormone, inactive or less active compound that can be converted into an active hormone through various metabolic processes.
what is vitamin D converted to and what by
converted to active 1,25 Dihydroxyvitamin D (calcitriol) by hydroxylations
what happens in the small intestine
1,25-dihydroxyvitamin D diffuses into enterocytes
It binds to the vitamin D receptor (VDR) and increases gene expression
This leads to an increase in the expression of apical Ca2+ channels and basolateral Ca2+ transporters
the ultimate effect is an enhancement of calcium transport across enterocyte membrane
what happens in the kidneys
1,25-dihydroxyvitamin D increases the expression of the Na+ -Pi cotransporter in the kidneys
It improves parathyroid hormone (PTH) - mediated Ca2+ reabsorption in the kidneys
What happens in the bones
1,25-dihydroxyvitamin D increases number of osteoclasts.
This likely influences bone remodeling processes as osteoclasts are involved in the breakdown of bone tissue.
where is calcitonin manufactred
in clear cells of the thyroid glands and plays a role in responding to hypercalcaemia but function in healthy individuals is probably very limited (thyriodectomy)
what do osteoclasts express?
they express calcitonin receptors and binding of calcitonin reduces the rate of bone turnover and therefore release Ca2+
what are other hormones involved in calcium homeostasis
sex hormones like oestrogen (responsible for maturation of bone into adulthood in both sexes) and testosterone (maintains bone destiny)
Glucocorticoid - regulate bone density and intestinal calcium absorption
parathyroid hormone-related protein (PTHrP) - mimics action of PTH in bones and kidneys but is produced outside the parathyroid glands.
Phosphatonins (Fibroblast Growth Factor 23 -FGF23)
FGF23 is a phsphatonin, a hormone that regulates phosphate homeostasis.
Primarily secreted by osteocytes in bone tissue.
FGF production is upregulated when plasma phosphate concentrations rise
FGF23 plays a role in promoting phosphate excretion in the urine, helping to lower plasma phosphate levels
Hypocalcaemia
Low plasma Ca2+
- total serum calcium <0.5 mmol l-1
- ionised serum calcium <0.3 mmol
what are some symptoms of hypocalcaemia
pins and needles
muscle spasms
paralysis
convulsions
hypercalcamia
High plasma Ca2+
- total serum >2.62 mmol l-1
- ionised serum calcium > 1.31 mmol l-1
what are some symptoms of hypercalcaemia
lethargy
depression
constipation
renal calculi
frequent urination
nausea
arryythmias
hypoparathyroidism
Lack of PTH due to lack of production of defects in the responsiveness of target tissue
symptoms of hypoparathyroidism
muscle spasm - tetany
low plasma calcium - hypocalcaemia
high inorganic phosphate - hyperphosphataemia
Hyperparathyroidism
Excess of PTH
Primary - Excess production of PTH from the parathyroid glands - tumors
secondary - chronic kindey disease i.e lack of 1,25 - dihydroxyvitamin D
- calcium malabsorption i.e. gastic bypass surgery
symptoms of hyperparathyroidism
hypertension
constipation
weakness
confusion
high plasma calcium - hypercalcaemia
summary
Calcium exists in homeostatic flux between bound, as hydroxyapatite and calcium phosphate and to calcium-binding proteins, and unbound, ionised, free calcium. Homeostatic control is tightly regulated because of the numerous and key physiological roles calcium plays within our bodies. The key regulators of calcium are:
* Metabolites of vitamin D (1, 25-Dihydroxyvitamin D)
* Parathyroid hormone (PTH)
* Calcitonin
However, PTH, released from parathyroid cells is the primary means by which calcium concentrations are regulated (in response to hypocalcaemia)
Other homeostatic events influence homeostasis of calcium, including sex hormones and glucocorticoids
