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APP > Calcium regulation > Flashcards

Calcium regulation Flashcards

1
Q

What three main hormones regulation Ca?

A

PTH
vitamin D metabolites.
calcitonin

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2
Q

What do the three hormones act on?

A

Kidney, gut and bone

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3
Q

How is Ca2+ stored in the body?

A

99% in bone

Rest in the form of simple phosphate salts

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4
Q

What is the normal range of calcium? What states is this calcium in?

A

2.4-2.6mM
50% is ionised and exists as free calcium
~40% is reversibly bound to plasma proteins
~10% exists as inorganic complexes with anions, esp phosphate and citrate

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5
Q

What is Ca required for?

A

EC coupling
synaptic transmission
platelet aggregation&coagultion
IC messenger

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6
Q

What may cause hypocalcaemia?

A

Often the result of secondary hyperparathyroidism due to chronic kidney disease
Excess plasma protein in multiple myeloma – reduces free Ca2+
Alkalosis: increase in negative charge on plasma proteins; more Ca2+ binds to protein; Ca2+ falls

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7
Q

Normal value of IC Ca

A

0.1uM

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8
Q

What can hypocalcaemia lead to?

A

neuronal hyperexcitability → lowered Ca2+ renders membrane slightly depolarised so it is more easily excited, additionally, certain Na+ channels are activated at these depolarised potentials, increasing Na+ permeability → tetany, which begins in the limbs, and may progress to convulsions.

The QT interval of the ECG is prolonged, and eventually heart failure occurs.

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9
Q

Treatment of hypocalcaemia?

A

initial calcium infusion, and long-term vitamin D administration to boost intestinal absorption.

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10
Q

Causes of hypercalcaemia

A

Often the result of primary hyperparathyroidism due to MEN (multiple endocrine neoplasia)
Loss of protein in nephrotic syndrome increases free Ca2+
Acidosis: decrease negative charge on plasma proteins; less Ca2+ bound to protein → hypercalcaemia

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11
Q

What does hypercalcaemia lead to?

A

Reduces neuron excitability slowing CNS activity
Insoluble calcium salts cause urinary stones and calcification of renal soft tissue which impairs renal function.
The body attempts to excrete the excess calcium via urine → polyuria, which leads to dehydration, and the large amounts of Ca2+ passing through the kidney lead to kidney stones

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12
Q

Treatment of hypercalcaemia

A

pamidronate – a BISPHOSPHONATE used to treat osteoporosis
Bisphosphonates inhibit bone resorption mainly by action on osteoclasts. They form tight complexes with Ca2+ in the bone matrix, and are released slowly as bone is resorbed by osteoclasts, which are thus exposed to high concentrations of the drugs

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13
Q

Main hormone for raising Ca levels

A

PTH

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14
Q

What is PTH secreted from and in response to?

A

Chief cells of parathyroid in response to decreased plasma Ca

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15
Q

How do chief cells sense Ca2+ and release PTH?

A

Falling plasma Ca2+ is sensed by the G protein-coupled Ca2+-SR (calcium sensing receptor) on chief cells. This process also requires magnesium
The calcium sensing receptor is coupled to both Gq and Gi proteins.
When no Ca2+ binds, the Gi protein is activated, initiating an intracellular cascade which induces PTH secretion
When Ca2+ binds the Ca-SR, the Gq protein is activated → stimulates phospholipase C → → ultimately leads to the activation of PKC which inhibits release of granules containing PTH and PTH synthesis

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16
Q

PTH action

A

PTH exerts its physiological effects via activation of the GPCR, the PTH1R – it is coupled to both adenylyl cyclase and phospholipase C (Gs and Gq-coupled)
PTH1R found on plasma membrane of osteoblasts and cells of proximal and distal tubules

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17
Q

Effect of PTH on kidneys

A

Acts to increase Ca2+ reabsorption in the distal tubule, prevents phosphate reabsorption
PTH binds to PTH1R in proximal renal tubule epithelial cells → inhibition of Na+-PO43- co-transport, and thus phosphate reabsorption from the proximal tubule. This has two major effects:

Raise free plasma Ca2+ by stimulating Ca2+ mobilisation from bone.

Less phosphate is available for the Ca2+ to bind to, thus a higher concentration of free calcium in the plasma.

Increased Ca2+ reabsorption is also stimulated in the DTs and CD independently of Na+
Increases the activity of 1α hydroxylase and thus increases synthesis of the active vitamin D metabolite: vitamin (1,25) D3, which has a role that will further be explored

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18
Q

Action of PTH on bone

A

BIPHASIC

  • Continuous stimulation = catabolic → leads to bone resorption → increase in plasma Ca2+
  • Has effects on osteoblast receptors:
  • Causes release of IL-6 which increased osteoclast activity & increases RANK-RANKL signalling which promotes differentiation of osteoclast precursors
  • Intermittent stimulation : Anabolic → positive effects of bone volume and microarchitecture → leads to decrease in plasma Ca2+
19
Q

What does vitamin D do to whole body Ca?

A

Raises it

20
Q

Describe vitamin D metabolism

A

Vitamin D3 (cholecalciferol) can either be synthesised in the skin (under the influence of UV light) or absorbed from our diet. It is then transported to the liver where it undergoes 25-hydroxylation by one of 2 hepatic enzymes (CYP27A1 or CYP2R1) to form calcifediol. During transport through the circulation, it is bound to a carrier protein (DBP). The calcifediol-DBP complex passes through the glomerular filter and is scavenged from the primary urine by the apical megalin receptor of the PT. Here, calcifediol is 1α-hydroxylated to the active vitamin D metabolite, calcitriol.

21
Q

What do most actions of vitamin D stem from?

A

The fact that it binds to vitamin D response elements (VDR) in nuclei of target cells

22
Q

Actions of vit D on intestine

A
  • stimulates absorption of Ca through both genomic and nongenomic mechanisms
  • Ca enters microvllius of the intestinal epithelial cell through TRPV6
  • binds calmodulin in the microvillus
  • this is attached to brush bored myosin which moves the calcium to calbindin which is transported in endocytic vesicles to basolateral membrane where it leaves through Ca-ATPase
  • vitamin D enhances this by inducing TRPV6, CaBP and Ca-ATPase, as well as increasing the amount of CaM bound to brush-border myosin in the brush border
23
Q

Actions of vit D on the kidney?

A

Has TRPV5 and Ca-ATPase (like the intestine) → vitamin D increases activity, calbindin also induced by vitamin D → leads to reabsorption
Phosphate reabsorption is mediated at the brush border by sodium-dependent phosphate transporters which rely on the basolateral Na/K-ATPase to maintain Na+ gradient → it is not clear whether vitamin D regulates the expression or activities of these transporters (as it does in the intestine), although it is known that PTH block reabsorption

24
Q

Effects of vitamin D on bone

A

Complex action result of direct and indirect effects

Net effect is to cause the increased flux of Ca into bone - this is due to the effect on the kidneys and GI system to increase reabsorption/absorption to increase plasma [Ca] which increases the available Ca to mineralize unmineralized osteoid

The direct effect is to mobilize Ca from bone; both osteoblast and osteoclast precursors have VDRs

Osteoblasts produce certain proteins; alkaline phosphatase, collagenase, plasminogen activator

Promotes development (with PTH) of osteoclasts from precursors, increasing the number of mature osteoclasts which can liberate Ca

The direct effect on bone contradicts the overall effect on bone which is to promote mineralization

25
Q

Summary of vitamin D effects

A

Increases whole body Ca

Acts via nuclear receptors which regulate transcription

Intestine; increases uptake of Ca by upregulating calbindin, Ca channel, NCX and Ca-H ATPase synthesis

Kidney; facilitates conservation of Ca and phosphate

Bone; inhibits synthesis of collagen by osteoblasts, and increases osteoclast bone breakdown

26
Q

What effects does vitamin D have that may not involve Ca directly?

A
  • regulation of hormone secretion (e.g. stimulates insulin secretion and vitamin D stops PTH secretion)
  • regulation of proliferation and differentiation (anti-cancer)
  • immune system (enhances innate and inhibits adaptive)
27
Q

what secretes calcitonin? what is it released in response to?

A

Thyroid C cells

Raised plasma Ca

28
Q

What does calcitonin do?

A

Lowers levels

29
Q

Action of calcitonin

A

Mediated by GPCR called high affinity calcitonin receptor
cAMP signal transduction (but can also do PLC pathway which causes a release of Ca2+ from intracellular stores and promotes influx of extracellular Ca2+)

30
Q

What does calcitonin do in the kidney?

A

increase excretion of calcium and phosphate

31
Q

What does calcitonin do in the gut?

A

Helps to control the rise inp plasma calcium immediately following a meal, may also inhibit absorption

32
Q

What does calcitonin do in bone?

A
  • inhibit osteoclast differentiation, reducing bone resorption and release of calcium and phosphate into the plasma
33
Q

Which groups accumulate Ca at a fast rate?

A

Children and pregnant women and lactating women

for growth, foetal development or to accommodate Ca loss in milk

34
Q

Which individuals undergo net Ca loss?

A

Elderly individuals

35
Q

What do osteoblasts do?

A

promote bone formation

36
Q

What do osteoclasts do?

A

promote bone resorption

37
Q

what do osteocytes do?

A
  • mature osteoblasts which have secreted a matriculates around them and become encased
  • sense mechanical stress through their long cellular processes (which form a lattice) and secrete GFs to stimulate osteoclasts and lining cells which can differentiate into osteoblasts
38
Q

What effect does vitamin D have on PTH?

A

Can stimulate its production

39
Q

What does PTH1R do in PCT cells?

A

Stimulates the final stage f vitamin D processing, where 25-hydroxyvitamin D is hydroxylated to form 1,25-hydroxyvitamin D (calcitriol)

40
Q

Summarise PTH effects

A

Raise lowered plasma [Ca]

Kidney

Inhibition of Na-phosphate cotransport and phosphate reuptake in order to drive Ca reabsorption in the distal renal tubular segments

Increases the synthesis of calcitriol through activity of 1-alphahydroxylase [in proximal segments]

Bone

Intermittent PTH secretion promotes bone growth and deposition

Constituitve PTH secretion causes osteoclast activity to increase (indirectly through osteoblast activation of osteoclast) which degrade bone.

41
Q

Summary of action of calcitonin

A

Prevents hypercalcemia and excess bone breakdown

Acts through Gs coupled receptors

Bone; decreases osteoclast activity, inhibiting mineral resorption and thus prevents additional hypercalcemia, whilst stimulating phosphate uptake to bone

Gut; helps control rise in plasma Ca due to absorption, inhibiting absorpiton of Ca

42
Q

Describe osteoporosis

A

Disease where the balance between osteoblast and osteoclast is disrupted leading to excessive resorption and progressive weakening of bones, and a consequential increased susceptibility to fracture after small trauma

In elderly individuals a concern is hip fracture, which results in immobility and is not good for overall health

The disease is most common in elderly, post-menopausal women due to the lack of estrogen in their circulation. Estrogen prevents resorption through acting on a receptor on osteocytes and osteoblasts, inhibiting their apoptosis, and inhibiting RANKL secretion whilst promoting OPG secretion to increase deposition and decrease resorption of bone.

HRT has been shown to be effective in reducing the risk of osteoporosis onset, with some individuals who refuse estrogen being offered calcitonin which also promotes bone formation

43
Q

Describe osteomalacia

A

Softening of bones caused by impaired bone metabolism due to inadequate levels of phosphate, calcium of vitamin D

Osteomalacia in children = rickets

Most common cause is vitamin D deficiency (can also be caused by vitamin D receptor mutations etc)

  • lack of calcification of bone matrix and remodelling
  • vitamin D preparations can be given as treatment

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