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BIOL31571 > Lecture 1 - Control of extracellular calcium homeostasis > Flashcards

Lecture 1 - Control of extracellular calcium homeostasis Flashcards

1
Q

Hypocalcaemia: what is it, what symptoms are present with it, and what signs are medically used to detect it?

A

Low blood calcium levels

Increased nerve excitability - Tetany (spasms), severe forms can cause death by asphyxiation

Chvostek sign
Trousseaus sign

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2
Q

Chvostek’s sign: what is it?

A

Twitching of facial muscles in response to tapping over the facial nerve

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3
Q

Trousseaus sign

A

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

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4
Q

Hypercalcaemia: what is it and what symptoms are there for it?

A

Too high blood calcium levels

  • Neuromuscular excitability leading to cardiac arrhythmias, lethargy, death
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5
Q

Calcium stores: what types are their, where are they located, and what percentage of the body’s calcium storage do they contribute to?

A

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%

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6
Q

Ca²⁺ homeostasis: what is it maintained by and what is the primary regulating endocrine organ?

A

The balance of net dietary intake and urinary excretion

Parathyroid glands - four glands located in the neck

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7
Q

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⁺?

A

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⁺

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8
Q

Why does increasing calcium resorption result in increased phosphate excretion?

A

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

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9
Q

Daily pulsatile PTH secretion: what does it do?

A

Results in mineralised bone formation

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10
Q

Sustained increases in PTH secretion: what does it do?

A

Results in demineralised bone formation

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11
Q

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?

A

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

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12
Q

Teriparatide: what is it sold as and what is it?

A

Forteo

The first 1-34 amino acids of PTH

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13
Q

1,25(OH)₂ vitamin D₃: what is it, how is it produced, and what are its names as it is being produced?

A

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)
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14
Q

Hydroxylation into 1,25 (OH)₂D₃: how does it occur?

A

This final step is catalysed by 1α- Hydroxylase primarily in the renal proximal tubule

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15
Q

1,25(OH)₂D₃: what is it, what does it do, how does it do it, and how does it travel around the body?

A

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)

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16
Q

Intestinal Ca²⁺ absorption: where is it mostly absorbed and where is it reabsorbed?

A

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

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17
Q

TRPV5: what is it and what does it do?

A

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

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18
Q

TRPV6: what is it and what does it do?

A

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

19
Q

CalD28k: what is it, what does its name mean, why is it required, what does it do, and where is it in high abundance?

A

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

20
Q

CalD9k: what is it, what does its name mean, why is it required, what does it do, and where is it in high abundance?

A

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

21
Q

VDRs: what are they, what do they do, and what effects do they cause in organisms?

A

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

22
Q

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?

A

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)

23
Q

Vitamin D deficiency: what are some examples of conditions caused by its deficiency?

A

Rickets – Vitamin D deficiency due to inadequate intake of proVit, or, sun exposure

Chronic deficiency → 2oHPT, osteomalacia

24
Q

Ca²⁺ homeostasis: what calcitropic hormones are involved?

A

Calciotropic hormones:
* PTH - resorption/reabsorption
* VitD₃ - resorption/reabsorption
* Calcitonin - decreases resorption (redundant outside of ocean?)

25
Q

Can we taste calcium?

A

No, but if we are hypocalcaemic we prefer calcium-rich water, despite being unable to taste the calcium

26
Q

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?

A

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

27
Q

PTHrP: what is it, what does it do, and why can it be dangerous?

A

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

28
Q

The calcium receptor: what does it do, why is it beneficial, and what is its structure?

A

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?

29
Q

Types of CaRs

A
  • Type 1 CaR agonists
  • Type 2 CaR “agonists - positive allosteric modulators
  • CaR “antagonists” - negative allosteric modulators
30
Q

Type 1 Ca²⁺ receptor agonists: what does this mean and what are some examples?

A

Substances that initiate a response when bound to the calcium receptor

  • Divalent Cations - Ca²⁺, Mg²⁺
  • Spermine
  • Gd³⁺
  • Aminoglycosides (neomycin)
31
Q

Type 2 Ca²⁺ receptor “agonists”: what does this mean and what are some examples?

A

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
32
Q

Ca²⁺ receptor “antagonists”: what does this mean and what are some examples?

A

Substances that decrease the responsiveness of the calcium receptor to type 1 calcium agonists - negative allosteric modulators

  • Calcilytics: NPS-2143
  • Acidosis, phosphate
33
Q

Treatments for calcium disorders: what are some types, what do they do, and what conditions do they treat?

A

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

34
Q

Hyperparathyroidism: what is it, what is it secondary to, and what does it result in?

A

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

35
Q

Extraskeletal calcification: what can it be caused by and what is it treated by?

A
  • Hyperparathyroidism
  • Calciphylaxis

Cinacalcet (mimpara)

36
Q

Cinacalcet: what is it, what is it sold as, and what does it do?

A

Medication that results in decreased Ca²⁺ levels

Mimpara

Lowers serum PTH in ESRD (end-stage renal disease)

37
Q

PTH homeostasis: why is it so significant in renal patients?

A

Elevated PTH levels in renal patients are associated with increased hospitalisation

38
Q

Calciphylaxis: what is it and how lethal is it?

A

Calcific uremic arteriolopathy - extraskeletal calcification

Associated with a high mortality rate

39
Q

Calcimimetics: why may it be a favourable treatment option over vitamin D?

A

Once daily dosing may produce pulsatile PTH secretion changes that help improve bone mass - better than vitamin D which just slowly reduces PTH levels

40
Q

Osteoblasts vs osteclasts

A

b - build
c - not build

41
Q

Osteoclasts: what do they do?

A

Break down broken parts of bones - allows osteoblasts to come in and replace broken parts

42
Q

1) Jansen’s metaphyseal chondrodysplasia
(ER)

A

∙ Rare Autosom Dom disorder - short-limbed dwarfism.
∙ PTH1R GoF mutation ↑ cAMP levels.

43
Q

2) Blomstrand’s chondrodysplasia (ER)

A

∙ 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

BIOL31571 (17 decks)

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