L1: Calcium homeostasis

Around 99% of the the total calcium in the body is stored as (1 kg)

• Calcium phosphate salts in bones

Where is the rest of the calcium?

• mainly in cells

• sequested inside organelles

THEREFORE→ cytoplasmic [Ca2+] is very low

• arounf 0.1 microM

What does this very low Ca2+ conc provide

• steep gradient for calcium entry

• from organelles or from extracellular fluids

Importance of calcium: what happens to extracellular calcium

• binds to be fixed

• negative charges on the extracellular surface of plasma membranes

  • altering the actual size of the membrane potential

Importance of calcium: what is the importance of this surface charge screening

• calcium stabilizes the membranes of excitable cells

• → making it slightly more difficult to open ion channels

Importance of calcium: Hypocalcaemia

Concentrations <2.4 mM

• if it drops to around 1.5mM:

  • nervous system becomes progressivley excitable

  • → tetanic contraction of muscles

• SEVERE hypocalcaemia:

  • tetany of the laryngeal muscles and Asphyxiation

Death is immenant around 1mM

Isn’t this the opposite of what we expect?

Wouldn’t low Ca2+ mean less vesicles so less Neurotransmitter across synapses?

1. Low extracellular Ca2+

2. so proteins now have negative charges

3. charges proteins

4. more excitable channels

5. AP to muscles→

Importance of calcium: Hypercalcaemia

Concentration >2.4mM

• lead to depression of nervous and muscular activity

• If rise ABOVE 3mM

  • calcium salts precipitate out

    • E.g calcium phosphate or calcium oxalate kidney stones

• SEVERE: fatal → but this is unusual!

painful and unpleasant but not usually fatal!

Importance of calcium: What is Hypercalcaemia a result of

• primary hyperparathyroidism

Cycle of plasma calcium levels

1. 1000 mg ingested in gut

2. 350mg Absorbed

3. 150 secreted due to shed of epithelial cells

4. Bone is constantly making and eording bone

5. Sweat glands and kidney out

6. lost in faeces

→ overall a balance

Control of plasma calcium levels: Ca homeostasis involves 3 chemical messengers

1. parathyroid hormone

2. calcitriol

3. calcitonin

Control of plasma calcium levels: these messengers work on targets…

1. Gut→ absorb more or less calcium

2. Kidney→ modulate out high rate of reabsorption

3. Bone→ change balance between erosion and deposition

Control of plasma calcium levels: bone→ daily turnover of bone remodelling can change due to…

Greatly increased by:

1. bone repair

2. lactating

Challenges to calcium homeostasis

1. Pregnancy and lactation

2. Egg-laying

3. Poor absorption

4. Oxalate poisoning

1. Pregnancy and lactation

At height of nursing:

• secrete 500-600 mg calcidum per day into milk

  • x3 usual daily net intake

Dairy cows:

• lactation → milk fever

Pregnant dogs and cats

• subject to hypocalcaemic fits

  • → eclampsia

2. Egg-laying

• hen egg contain 2g of Ca

• calcium deposited as a special type of bone→ medullary bone

  • this calcium is mobilized to allow egg production to continue at night

3. Poor absorption

1. Vitamin D₃ Definiciency

   • result in difficulty absorbing dietry calcium

2. Dietry calcium can bind to phytates

   • in cerals, reducing absorption

4. Oxalate poisoning

Many plants accumulate oxalate as a defence

1. Calcium oxalate precipitates out in the gut

2. excreted

3. but, unbound oxalate can be absorbed→ leading to calcium oxalate crystals forming within the body too

4. RESULT→ hypocalcaemia and kidney stones

Sources:

• spinach, rhubarb, strawberries

Parathyroid hormone (PTH): features

• 84 amino acid polypeptide

• secreted by parathyroid glands

• ESSENTIAL for life

Ways to get calcium 

1. Gut→ increased absorption via D3

2. Kidney→ increased reabsorption (don’t lose as much)

3. Bone→ increased dissolution

Parathyroid hormone (PTH): features of its release

• circadian rhythm to its release

• released in pulses

• glands are innervated by autonomic nerves

  • → help to modulate the rhythms

Parathyroid hormone (PTH): What is the only significant external stimulus to promote increased PTH release

• decrease in plasma free calcium levels

Parathyroid hormone (PTH): Response to this

1. G1 protein linked calcium receptor → in plasma membrane

2. respond to increased free Ca in the plasma 

3. increasing internal calcium levels

4. Low extracellular calcium leads to

5. Low internal calcium levels

6. → usually promotes vesicular release:

   1. less Ca2+ causing vesicle release

   2. different SNARE

no nervous input→ WHYYYY???

Parathyroid hormone (PTH): Where does PTH work

1. bone

2. kidney

3. The gut→ via vit D3

→ to increase plasma calcium levels in a negative feedback system

PTH receptors are G-protein linked and located on the plasma membrane

PTH and bone: what do osteoblasts and bone remodelling

1. lay down organic matrix of bone

   • → composed of collagen and proteoglycans

2. Calcium phosphate salts precipitate on the collagen fibres

3. ultimately→ form hydroxapatite crystals Ca10(PO4)6(OH)2

4. Some osteoblasts become trapped within the bone and become→ osteocytes

PTH and bone: Osteocytes and osteoblasts Arrangement/strucuture

• connected by long processes

• running in tiny canals throughout the bone

  • → form continuous network of very large surface area

  • running throughout the bone

  • over its surface

• they separate bone fluid adjacent to the bone surface

PTH and bone: what is in this bone fluid

• high in calcium

• from ECF on the other side

PTH and bone: other feature of osteoblasts and cytes

• have membrane-bound PTH receptors

PTH and bone: Osteoclasts

• separate lineage of cells found within bone

• Giant, multinucleated

PTH and bone: Osteoclasts what do they do

• release proteolytic enzymes and acids

• help to digest an dissolve bone

→ helps in bone remodelling

PTH and bone: what does bone remodelling involve

1. bone reabsoprtion by the osteoclasts

2. deposition by osteroblasts

→ about 10% of adult bone is turned over each year

PTH and bone: PTH effects on bone

1. controversial: osterocytic osteolysis→ describes the erosion of nearby, easily-accessible bone crystals by osteocytes

   • taking advantage of their large SA

2. Calcium released

3. transferred into the ECF

4. mobilization is rapid→ minutes→ hours

5. ten min: osteoblasts are inhibited from laying down more bone

6. ostesoblasts produce a paracrine signal

7. stimulates the osteoclasts to erode bone

8. releasing more Ca into the ECF

9. Effect develops over days or weeks

10. the signal ALSO stimulates progenitor cells to differentiate into more osteroclasts

PTH increases bone erosion BUT PTH can be injected to treat osteroporosis?!

• Because the type of injection of hormone 

• Injected=> BIG SPIKE

• decreases bone erosion

Parathyroid hormone and the kidney: three effects of PTH on the kidney, acting on different parts/functions

1. Distal convoluted tubule

2. Proximal tubule

3. Active vit D3

Note: there is always Ca2+ reabsoprtion in the PCT and LoH

• the PTH just tweaks the control

PTH effects levels of what in the kidney?

1. Promotes Ca2+ reabsorption

2. Inhibits Phosphate reabsorption

Parathyroid hormone and the kidney: three effects of PTH on the kidney: effect 1

1. PTH increases active reabsorption of Ca by the distal convoluted tubule of the kidney

2. The trancellular calcium transport mechanisms resemble those in the gut

3. effects of PTH are very fast acting within minutes

4. allow rapid adjustments to blood calcium levels

Parathyroid hormone and the kidney: three effects of PTH on the kidney: effect 2

1. PTH powerfully inhibit reabsoprtion of inorganic phosphate Pi ions in the proximal tuule

2. Helps to lower extracellular phosphate levels

inhibits Pi reabsorption so can dump the Pi AFTER is has been eroded by the bone→ OVERALL selects for Ca2+ in this bone erosion

Parathyroid hormone and the kidney: three effects of PTH on the kidney: effect 3

1. PTH stimulates syntehsis of active vit D3 derivative calcitriol (1,25(OH)2D)

2. has an important role in the intestinal absorption of calcium

OVERALL: in the presence of PTH

1. calcium is released from bone 

2. plasma levels rise

3. Phosphate levels:

   • although phosphate absorption from gut and bone is increased

   • this effect is overwhelmed by the increased loss of phosphate

   • in the urine

• ALSO: drop in phosphate→ MORE free Ca because it is no longer bound to phosphate

→ OVERALL: net phosphate is lost

Vitamin D3 and derivatives: Vitamin D3 (Cholecalciferol) how made/obtained

1. in specialised skin cells→ keratinocytes

   • from cholesterol

   • In one step of synthesis: Secosteroid requires exposure to UVB light

2. Obtained in diet

   • dairy products and fish liver oils

   • Vegans→ supplement of the equivalent vit D2→ made of fungal sterol ergosterol

the strucutrue of Vit D3 is close to cholesterol

Vitamin D3 and derivatives: where/how stored (in what form)

1. Stores in liver

   • used to maintain a constant level of 25-hydroxycholecalciferol (25-OHD) in plasma

   • after enzymatic conversion subject to feedback control

2. Proximal tubules of the kidney

   • taken up under the influence of PTH

   • decreased clacium leveles/decreased pohsphate levels→ converted to biologically ACTIVE form calcitriol (1,25 dihydroxycholecalciferol; 1,25(OH)₂D)

3. Otherwise→ converted into inert 24,25(OH)₂D

25-OHD→ is the main form in plasma bound to proteins

Vitamin D3 and derivatives: Roles of calcitriol are mediated by

• ts nuclear receptor

Functions of calcitriol

1. Increase Ca absorption from gut

2. promotes erosion of bone

3. INcreases Ca and phosphate reabsorption from kidney

Vitamin D3 and derivatives: calcitriol most important effect

Increase calcium absorption from gastrointestinal tract:

• in the Duodenal epitheial cells→ 

  1. calcitriol upregulates expression of an apical calcium channel→ calbindin protein

  2. ferries calcium across the cell

  3. basolateral Ca2+-ATPase pumps it out into extracellular fluid

  4. Phosphate absorption from the gut is also increased

Vitamin D3 and derivatives: calcitriol minor roles…

1. promote bone erosion

2. increasing both Ca and phosphate reabsorption from the kidney

In what ways are vitamin D3 less like a ‘true’ vitamin and more like a steroid hormone?

• kinda both

• Vitamin→ its is REQUIRED for normal physiologyical process and cannot be made

• Steroid hormone→ chemmical messenger from cholesterol, travel in the blood and works on intracellular receptors and affects gene expression

Vitamin D deficiency: Rickets

• in children dietary lack of vitamin D3 is the commonest cause of rickets:

1. plasma calcium do not drop substantially because of PTH secretion

   • which erodes the bones to maintain plasma levels

2. but the weakened bones become distorted

Vitamin D deficiency: Adult version of rickets

• after grwoth-plates fuse

• osteromalacia

Factors affecting Vit D3 availability

1. Latitude, air pollution, clothing, sunblock

2. Vegan diets

3. Women vs men??→ Women are paler?→ need more Ca for pregnancy?

4. Steatorrhoea→fatty faeces→ lose D3 with as fat soluuble→ decrease Ca2+too coz not enough fat

What is calcitonin

• 32 amino acid polypeptide hormone

• secreted by the C-cells (clear cells) of the thyroid

Primary stimulus of calcitonin secretion

1. increased plasma [Ca} levels acting directly on the C-cells

Effect of calcitonin

1. reduces plasma [Ca] 

2. by rapidly inhibiting the erosion of bone by osteoclasts

3. shifting the balance in favour of deposition

Gastrin→ what does it do

• causes increased calcitonin secretion

  • might help as an anticipatory response to the calcium

  • that will be absorbed as part of the meal

but this is controversial as the concentrations needed are not physioligcally possible

It has been suggests that calcitonin helps to…

• Stabilise Ca2+ homeostasis when turnover between plasma and bone is unusually high

  • e.g during growth or lactation

• To protect against excessive bone erosion

However…

• some argue that calcitonin has no important physiological effcts in humans

→ may be a vistigial hormones→ when the thyroid is removed→ still get normal calcitonin

How else can humans deal with hypercalcaemia? Why is calcitonin more important in marine fish?

• Caclitonin is used more or less depending on the environment of the organism

  • → e.g marine fish

  • importnat to stop hyper Ca due to the gills being exposed to water

  • which will be high in Calcium

  • so therefore it is importantn in controlling the Ca2+ levels

Phosphate homesostais: phosphate importance

1. essential as part of the inorganic structure of bone

2. As part of many organic molecules

Phosphate homesostais: phosphate in the plasma

• present mainly in the forms HPO₄^2- and H₂PO_4-

Phosphate homeostasis and calcium

• phosphate homesostasis is closely linked with that of calcium

You have enough information from these notes for you to work out the body’s response to low phosphate levels. Draw out a flow diagram to illustrate the processes involved. Consider the effects on calcium levels too!

put this here lol

Exam questions

1. Compare the roles of parathyroid hormone, vitamin D and calcitonin in the regulation of blood calcium levels (NST 1B 1994)

2. What mechanisms contribute to the stability of the plasma concentration of free calcium ions? (NST 1B 1996)

3. Explain why parathyroid hormone, but not calcitonin, is essential for life (NST 1B 2000)