Roles of calcium in the body?
There are 8
- Bone and teeth rigidity
- Muscle contraction
- Membrane stability
- Neurotransmitter & hormone release
- Secretory processes
- DNA/RNA synthesis
- Blood clotting
- Enzyme regulation.
Low extracellular calcium levels.
Nervous system becomes progressively more excitable as the increased in permeability for sodium ions.
Hyperexcitability causes muscle contraction and cramps
Poor mineralisation of bones.
Leads to rickets in children.
If calcium get too low: uncontrolled and intense muscles spasms.
High extracellular calcium level.
Moans, Stones, Groans and Bones
Moans: gastrointestinal conditions such as constipation.
Stones: kidney-related conditions such as kidney stones.
Groans: Psychological conditions such as confusion.
Bones: Bone pain and bone-related conditions such as bone aches & pains.
Primary regulators of calcium balance?
Vitamin D (The sun hormone)
What does PTH, Calcitonin and vitamin D do?
What 3 organs do they regulate this function in?
Regulate calcium reabsorption, absorption and excretion from the kidney, intestine and bone.
What name is also given to vitamin D?
Explain the hormones that take part in regulating calcium balance?
Parathyroid hormone (PTH)?
Produced by Chief cells of the parathyroid glands.
Stored as pre-pro or pro-hormone.
Target organs are bone and kidney.
Small clusters of cells outwith the thyroid which also excretes this hormone (alog the trachea)
Interaction between PTH and CaSR?
PTH secretion is controlled by extracellular calcium-sensing recepotr CaSR.
CaSR is a GPCR on the surface of parathyroid cells.
How does high/low levels of calcium effect PTH production?
CaRH binds calcium
If calcium is present: this inwards uptake of calcium leads to the PTH secretion to be inhibited.
If calcium is absent: calcium is not bound to CaRH and no inhibition occurs. PTH is secreted and PTH action leads to increase of calcium.
No longer calcium homeostatic
Excressive PTH secretion.
Intestinal calcium absorption and renal tubular reabsorption
Inadequate response of the vitalime D-PTH axis to hypocalcemic stimuli.
32 AA polypeptide
Released from the thyroid gland-parafollicular cells.
Hypercalcaemic in action.
Antagonist in action to PT-release in response to high Ca levels.
Increase production of inactive vitamine D.
Interaction between PTH and Calacitonin vs plasma concentration?
As plasma concentration levels of calcium increase PTH levels decrease and there is a rise in calcitonin levels.
Target cell for calcitonin?
How does calcitonin do its action?
Calcitonin acts on specific GPCR to increase cAMP conc.
Inhibits osteoclast motility, shape and inactivates them.
Rapid fall in calcium caused by inhibition of bone reabsorption.
Balancing act between PTH and Cacitonin.
How do we acquire vitamin D?
Produced in the skin by ultraviolet radiation
Ingested in the diet
Why cant we not use vitamin D directly?
What has to happen first?
Vitamin D itself is inactive
Has to be converted to active metabolite, 1,25-dihydroxyvitamin D3.
Active vitamin D is considered a hormone as it acts on distant target cells (not a classic hormone as it is not secreted by an endocrine gland).
In which organ does this convertion from vitamin D to 1,25-dihydroxycholecalciferol (calcitriol).
First UV light is absorbed in the skin by cholecalciferol vitamine D3.
It is then converted to 25 hydroxycholecalciferol in the liver.
Convertion into 1,25-dihydroxycholecalciferol in the kidney.
All the names for active vitamin D?
1,25- Dihydroxyvitamin D3.
What is the role for vitamin D?
Regulator of calcium.
Increase calcium absorption fron the intestine and reaborption from the bone.
How does active vitamin D travel?
What receptor does it bind to?
It is a lipid soluble hormone that binds to nuclear receptor (VDR)
Travels the blood bound to hydroxylated alpha-globulin.
Many target genes
Vitamin D action on bones?
OSTEOBLASTS contains vitamin D (not osteoclasts)
Calcitriol act on osteoblasts which produce a paracrine signal that activate osteoclasts to resorb calcium.
Difference between osteoblasts and osteoclasts?
Osteoblasts: cell in the body that build new bone tissue
Osteoclasts: Cells that break down and remove bone tissue.
What is calcium so important?
Diverse cellular function.
The presence of specific calcium transporters means that its cellular conc. can be precisely regulated.
What is the electrogradient for calcium? ie inside or outside.
What stops calcium passively diffusing?
calcium electrogradient influx.
Membrane stops the calcium passively entering
What intracellular stores are there for calcium?
Why are these needed?
Mitchondria and smooth ER.
Used to maintain low conc of calcium in the cell.
Control of free cystolic calcium?
Calcium is actively pumped out the cell
Electrogradient of calcium is to enter.
To maintain low levels of calcium inside the cell: mitchondria and smooth ER are stores for calcium.
2 influx mechanisms for calcium?
Calcium entry via ligand-gated calcium cannels
Can leak through passive bilayer diffusion via gap junctions.
Voltage-sensitive calcium channels allows calcium to
enter or exit the cell?
Can use patch clamp to measure flow of ions.
Name the 4 types of voltage-sensitive calcium channels?
What is the current needed to activate each one?
Length of time before inactivation?
L-type: strong depolarising current activates, long duration. Inhibited by nifedipine.
T-Type: weak depolarising current activates, rapidly inactivated. Insesnitive to inhibitors of L-type.
N-type: requires strong depolarising current. Inactivation rapid. Insenstive to DHP inhibitors but not conotoxin.
P-type: medium depolarising current. Not inhibited by DHP inhibitors or conotxin but sensitive to spider toxin.
What are the characteristics of a receptor activated calcium-influx?
A channel that is activated in response to intracellular messenger such as IP4 or calcium itself.
Activated in response to interaction with a G-protein.
Two mechanisms by which calcium efflux may occur?
Characteristics of the calcium/sodium exchanger
Facilitates rapid outflow of calcium that enters through voltage-gated calcium channels.
Energy provided by sodium gradient.
Electroneutral (transfer 2H for 2Ca).
Extrudes calcium against its gradient therefore requires ATP.
Function is to maintain basal intracellular calcium.
Calmodulin enhances affinity and rate.
Calcium binding proteins?
Contribute to the calcium-buffering capacity
Activity of these proteins is directly affected by changes in cytosolic calcium
Name the 2 classes of calcium modulated proteins?
- Those with helix-loop-helix (HLH) structures
- Those without HLH structures.
eg. HLH: calmodulin
without HLH: PKC
What is this HLH structure?
12 amino acid residue flanked on either side by a helical arrangement.
eg. calmodulin has 4 HLH motifs allowing 4 calcium ions to bind.
How does the HLH site bind to calcium?
Charge contact: because of its 2 positive charges.
Calcium also has a very unique ionic radius that can allow binding.
Name the 4 biological processes affected by calcium modulated proteins?
- Activaton of calcium-sensitive Adenylate cyclase.
- Calmodulin-activated phosphodiesterase.
- Troponin C and skeletal muscle contraction.
- PK converts phosphorylase inactive b-form to active a-form.
The phosphatidylinositol lipid cycle?
Used to regulate calcium concentration inside the cell.
Responsible for initiating PI hydrolysis.
PIP2-> IP3 and DAG
Regulation of PLC activity by substrates?
Large amounts of phosphatidylcholine inhibit PLC.
Phosphatidylserine and DAG oppose this effect.
Regulation of PLC activity by G proteins?
In some cells pertussis toxin which ADP Gi inhibit PLC acitivty.
Addition of GTPgammaS results in PLC activation
Uptake and release of calcium?
In permeabilised pancreatic acinar cells.
IP3 induces calcium released from intracellular pools
IP3 and calcium?
Either be broken down to yield inositol or can be used to phoshorylate to IP4.
Has 2 fates.
Either be degraded to inositol or may fulfil some 2nd messenger function
Name some effectors regulated by calcium?
In the ER.
Interacts with the Orai1 teramer receptor in the PM
causes calcium to enter the cell.
Used to replenish the stores.
STIM dimers (two are needed to make the receptor) translocate when calcium is depleted to make the STIM receptor