Lecture 1 - Control of extracellular calcium homeostasis Flashcards
Hypocalcaemia: what is it, what symptoms are present with it, and what signs are medically used to detect it?
Low blood calcium levels
Increased nerve excitability - Tetany (spasms), severe forms can cause death by asphyxiation
Chvostek sign
Trousseaus sign
Chvostek’s sign: what is it?
Twitching of facial muscles in response to tapping over the facial nerve
Trousseaus sign
Involuntary contraction of the muscles in the hand and wrist (i.e., carpopedal spasm) that occurs after the compression of the upper arm with a blood pressure cuff
Hypercalcaemia: what is it and what symptoms are there for it?
Too high blood calcium levels
- Neuromuscular excitability leading to cardiac arrhythmias, lethargy, death
Calcium stores: what types are their, where are they located, and what percentage of the body’s calcium storage do they contribute to?
Insoluble - bones and teeth - 99%
Intracellular soluble - cytosol and nucleus - <0.1%
Intracellular insoluble - Plasma membrane, mitochondria, ER, and other organelles - 0.9%
Extracellular soluble - extracellular fluid - 0.1%
Ca²⁺ homeostasis: what is it maintained by and what is the primary regulating endocrine organ?
The balance of net dietary intake and urinary excretion
Parathyroid glands - four glands located in the neck
PTH: what is it, what is its receptor, where is it produced, how is it produced, what does it do, and how does its secretion relate to serum Ca²⁺?
Parathyroid hormone
PTH receptor - a GPCR
Chief cells of parathyroid gland
PTH is an 84 αα hormone but synthesised as:
* Pre-pro PTH (115 αα)
* ProPTH (90 αα)
* 1-84 PTH (t1/2 < 20 mins)
Elevates plasma Ca²⁺ levels by:
* Increased bone resorption
* Increased renal Ca²⁺ reabsorption i.e. decreased excretion (but also increased Pi excretion)
* Increased production of 1,25(OH)2D₃ (Vit D)
PTH secretion is inversely proportional to serum Ca²⁺
Why does increasing calcium resorption result in increased phosphate excretion?
They are stuck together in the form of hydroxyapatite - for calcium to be resorbed, phosphate has to be removed so that they don’t crystallise in the blood
Daily pulsatile PTH secretion: what does it do?
Results in mineralised bone formation
Sustained increases in PTH secretion: what does it do?
Results in demineralised bone formation
Treatment of post-fracture osteoporosis: what is an example that is not bisphosphonates, what does it do, how is it used, and when is it recommended?
Teriparatide (Forteo), PTH 1-34
Anabolic for bone. decrease vertebral & non-vertebral fractures in postmenopausal women with osteoporosis
Self-injected (Thigh/Abdomen, requires training) - s.c. 20 μg/day for 24 months max. £3.5k p.a.
Recommended where alendronate / risedronate not tolerated or following unsatisfactory response
Contraindicated with hypercalcaemia, and small, transient increase in serum calcium possible
Teriparatide: what is it sold as and what is it?
Forteo
The first 1-34 amino acids of PTH
1,25(OH)₂ vitamin D₃: what is it, how is it produced, and what are its names as it is being produced?
Calcitriol - the active form of vitamin D
- Cholesterol moves into the intestines where it becomes Pro-vitamin D₃ (7-dehydrocholesterol)
- ProVD₃ moves from the intestines to the skin where it becomes a secosteroid as one of its bonds is broken by the sunlight, forming vitamin D₃
- Vitamin D₃ then moves to the liver where there is constitutive hydroxylation of VD₃ at the 25 position, forming 25(OH)D₃ (calcifediol)
- 25(OH)D₃ then moves to the kidney where a controlled process, dependent on PTH, hydroxylates calcifediol at the 1 position, forming 1,25 (OH)₂D₃ (calcitriol)
Hydroxylation into 1,25 (OH)₂D₃: how does it occur?
This final step is catalysed by 1α- Hydroxylase primarily in the renal proximal tubule
1,25(OH)₂D₃: what is it, what does it do, how does it do it, and how does it travel around the body?
Calcitriol - the active form of vitamin D
Increase Ca²⁺ levels by:
* Increasing net intestinal Ca²⁺ uptake from 200 to as much as 600 mg/day - increases calbindin expression (D9k and D28k)
* Increasing bone resorption (same function as PTH)
* Increasing renal Ca²⁺ reabsorption (same function as PTH)
Vit D₃ (& its –OH derivatives) are lipid soluble and so are carried in the plasma bound to specific globulin VitD binding protein (DBP)
Intestinal Ca²⁺ absorption: where is it mostly absorbed and where is it reabsorbed?
90% of dietary Ca²⁺ absorbed in the duodenum, both paracellularly (passive), and, transcellularly (active) requiring 1,25(OH)2D₃
Very similar in renal DCT except TRPV5 predominant, and calbindin-D28k replaces D9k, needs 1,25(OH)2D₃
TRPV5: what is it and what does it do?
Transient receptor potential cation channel subfamily V member 5
Channel proteins in the renal cell membranes allowing for Ca²⁺ to pass through into the cell
TRPV6: what is it and what does it do?
Transient receptor potential cation channel subfamily V member 6
Channel proteins in the intestinal cell membranes allowing for Ca²⁺ to pass through into the cell
CalD28k: what is it, what does its name mean, why is it required, what does it do, and where is it in high abundance?
Calbindance - calcium-binding proteins
(Cal)cium vitamin (D) dependent (28) (k)ilodalton protein
Sustained intracellular Ca²⁺ can drive calcium overload and apoptosis, cells reabsorbing calcium need a mechanism to prevent this
Captures Ca²⁺ and carries it across the cell to active pumps to send calcium into the blood
High abundance in renal cells
CalD9k: what is it, what does its name mean, why is it required, what does it do, and where is it in high abundance?
Calbindance - calcium-binding proteins
(Cal)cium vitamin (D) dependent (9) (k)ilodalton protein
Sustained intracellular Ca²⁺ can drive calcium overload and apoptosis, cells absorbing calcium need a mechanism to prevent this
Captures Ca²⁺ and carries it across the cell to active pumps to send calcium into the blood
High abundance in intestinal cells
VDRs: what are they, what do they do, and what effects do they cause in organisms?
Vitamin D receptors
Activation of nuclear VDR results in transcriptional regulation of vitamin D-responsive genes
VDR knockout mice exhibit no abnormalities before
weaning but after weaning exhibit:
* Impaired bone formation
(= vitamin D-dependent rickets type II)
* Uterine hypoplasia
* Failure to thrive
* Hypocalcaemia
* Growth retardation
* Alopecia
* Infertility
Calcium sources: how do humans gather it, how do marine organisms obtain it, and what are the differences in calcium intake between marine and terrestrial organisms?
Dietary Sources – Lipid soluble:
* Oily Fish e.g. salmon
* Dairy (variable)
* Leafy greens
* Nuts and seeds
* Oranges
Ocean - calcium-rich environment, harder to remove calcium than taking it in
Organisms in the ocean focus on removing calcium while terrestrial focus on gaining calcium (using UVR to make vitamin D to take more calcium in)
Vitamin D deficiency: what are some examples of conditions caused by its deficiency?
Rickets – Vitamin D deficiency due to inadequate intake of proVit, or, sun exposure
Chronic deficiency → 2oHPT, osteomalacia
Ca²⁺ homeostasis: what calcitropic hormones are involved?
Calciotropic hormones:
* PTH - resorption/reabsorption
* VitD₃ - resorption/reabsorption
* Calcitonin - decreases resorption (redundant outside of ocean?)
Can we taste calcium?
No, but if we are hypocalcaemic we prefer calcium-rich water, despite being unable to taste the calcium
PTHRs: what are they, what are their key features, where are they mainly present, what do they do, and what pathways do they interact with?
Parathyroid hormone receptors
- 7-TM protein (GPCR)
- Unusually large extracellular domain
High expression in bone and kidney
Mediates endocrine PTH effects and paracrine effects of PTHrP
Couples to the Gs / AC / cAMP / PKA
pathway - can also stimulate Gq / PLC
pathway with lesser potency/efficacy
PTHrP: what is it, what does it do, and why can it be dangerous?
Parathyroid hormone-related protein
Act in a similar way to PTH
Some tumours may pump it out, causing it to act like PTH and cause hypercalcemia
The calcium receptor: what does it do, why is it beneficial, and what is its structure?
Inhibits PTH secretion from the parathyroid gland
Allows for tightly regulated calcium homeostasis
7-TM GPCR, contains clusters of negatively charged amino acids: Ca²⁺ binding?
Types of CaRs
- Type 1 CaR agonists
- Type 2 CaR “agonists - positive allosteric modulators
- CaR “antagonists” - negative allosteric modulators
Type 1 Ca²⁺ receptor agonists: what does this mean and what are some examples?
Substances that initiate a response when bound to the calcium receptor
- Divalent Cations - Ca²⁺, Mg²⁺
- Spermine
- Gd³⁺
- Aminoglycosides (neomycin)
Type 2 Ca²⁺ receptor “agonists”: what does this mean and what are some examples?
Substances that increase the responsiveness of the calcium receptor to type 1 calcium agonists - positive allosteric modulators
- Calcimimetics: R568, Cinacalcet, etelcalcitide
- Aromatic Amino Acids: L-Trp, L-Phe
Ca²⁺ receptor “antagonists”: what does this mean and what are some examples?
Substances that decrease the responsiveness of the calcium receptor to type 1 calcium agonists - negative allosteric modulators
- Calcilytics: NPS-2143
- Acidosis, phosphate
Treatments for calcium disorders: what are some types, what do they do, and what conditions do they treat?
Calcimimetics - positive allosteric modulator of the calcium receptor:
* Decrease PTH secretion
* Used For treatment of primary & secondary hyperparathyroidism
Calcilytics - negative allosteric modulator of the calcium receptor (Ca²⁺ antagonist)
* Increase PTH secretion
* Proposed use to treat CaR gain-of-function mutations (ADH1)
* Originally used as possible treatment for osteoporosis, not still used as they reduce bone resorption but don’t promote bone formation
Hyperparathyroidism: what is it, what is it secondary to, and what does it result in?
Excess PTH hormone production
Secondary to renal failure
Pulling minerals out of bone - ends up in other parts of the body like soft tissues and muscle
Extraskeletal calcification: what can it be caused by and what is it treated by?
- Hyperparathyroidism
- Calciphylaxis
Cinacalcet (mimpara)
Cinacalcet: what is it, what is it sold as, and what does it do?
Medication that results in decreased Ca²⁺ levels
Mimpara
Lowers serum PTH in ESRD (end-stage renal disease)
PTH homeostasis: why is it so significant in renal patients?
Elevated PTH levels in renal patients are associated with increased hospitalisation
Calciphylaxis: what is it and how lethal is it?
Calcific uremic arteriolopathy - extraskeletal calcification
Associated with a high mortality rate
Calcimimetics: why may it be a favourable treatment option over vitamin D?
Once daily dosing may produce pulsatile PTH secretion changes that help improve bone mass - better than vitamin D which just slowly reduces PTH levels
Osteoblasts vs osteclasts
b - build
c - not build
Osteoclasts: what do they do?
Break down broken parts of bones - allows osteoblasts to come in and replace broken parts
1) Jansen’s metaphyseal chondrodysplasia
(ER)
∙ Rare Autosom Dom disorder - short-limbed dwarfism.
∙ PTH1R GoF mutation ↑ cAMP levels.
2) Blomstrand’s chondrodysplasia (ER)
∙ Rare Autosom Rec disorder - early lethality and advanced bone maturation.
PTH1R inactivating mutations/deletions
↓PTH-induced cAMP formation.
PTH-1R k/o also leads to early lethality
