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Calcium
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- 1What are the roles of calcium?Bone and teeth rigidity
Muscle contraction
Membrane stability
Neurotransmitter release
Secretory processes
DNA/RNA synthesis
Blood clotting
Enzyme Regulation (Calmodulin) - 2What is hypocalcemia?When extracellular calcium falls below normal, the nervous system becomes progressively more excitable because of increased permeability of neuronal membranes to sodium ions
Hyperexcitability causes tetanic muscle contractions and cramps
Hypocalcemic tetany
Chronic hypocalcemia contributes to poor mineralization of bones and osteoporosis.
In children, hypocalcemia leads to rickets and impaired growth (osteomalacia in adults).
If calcium gets really low: you will experience a painful death through uncontrolled & intense muscle spasms , epileptic seizures & bleeding (impaired clotting). - 3What are the symptoms of hypercalcemia?Moans (gastrointestinal conditions)
Constipation Nausea Decreased appetite Abdominal pain Peptic ulcer disease
Stones (kidney-related conditions)
Kidney stones Frequent urination
Groans (psychological conditions)
Confusion Dementia
Memory loss Depression
Bones (bone pain and bone-related conditions)
Bone aches and pains Fractures
Curving of the spine and loss of height
If way too much: abnormal heart rhythms, cardiac malfunction, death! - 4What are the primary regulators of calcium balance?Parathyroid hormone (PTH), 1,25-dihydroxy Vitamin D3 (Vitamin D3), and Calcitonin, regulate Ca2+ resorption, reabsorption, absorption and excretion from the, kidney, intestine and bone.
- 5Describe parathyroid hormoneManufactured in Chief cells of the parathyroid glands
Stored as pre-pro or pro-hormone, Cleavage of leader and pro-sequences yield a biologically active peptide of 84 aa.
Target organs are bone and kidney. Action on body is Hypercalcaemic
Thyroidectomy, which commonly removes the parathyroid gland also, would be fatal, except for the fact that there are small clusters of PTH producing cells,outside of the parathyroid gland, along the trachea. - 6How does CaSR work with PTH?PTH secretion is controlled by a unique extracellular calcium-sensing receptor (CaSR), a G protein-coupled receptor, on the surface of parathyroid cells.
CaSR activates phospholipase C and inhibits adenylate cyclase: this will increase intracellular Ca2+ via generation of inositol phosphates and decrease in cAMP, which prevents exocytosis of PTH from secretory granules. - 7Describe hyperparathyroidismCalcium homeostatic loss due to excessive PTH secretion
Due to excess PTH secreted from adenomatous or hyperplastic parathyroid tissue
Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal Ca2+ absorption and renal tubular reabsorption
Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-dihydroxyvitamin D3 . - 8Describe hypoparathyroidismHypocalcemia occurs when there is inadequate response of the Vitamin D-PTH axis to hypocalcemic stimuli.
Hypocalcemia is often multifactorial.
Hypocalcemia is invariably associated with hypoparathyroidism.
Bihormonal—concomitant decrease in 1,25-dihydroxyvitamin D3. - 9Describe calcitonin32-amino acid polypeptide released from Thyroid gland - parafollicular cells
It is hypocalcaemic in action
Antagonist in action to PTH, released in response to a rise in circulating Ca2+
Bone:- decreased activity of osteoclasts and osteoblasts
Increases production of inactive Vitamin D - 24,25DHCC
Little function in adult, no effects of deficiencies
Simple short loop feedback regulation
[CT] is proportional to [Ca2+] i.e. if [Ca2+] increases so does [CT]
As [Ca2+] falls the thyroid gland makes less CT - 10Describe the action of calcitoninThe target cell for calcitonin is the osteoclast.
Calcitonin acts on specific GPCR’s to increase cAMP concentrations. This inhibits osteoclast motility, changes in cell shape and inactivates them.
The major effect of calcitonin administration is a rapid fall in Ca2+ caused by inhibition of bone resorption. - 11Describe the synthesis of vitamin DHumans acquire vitamin D from two sources.
Vitamin D is produced in the skin by ultraviolet radiation and ingested in the diet. (Note difference between vitamin D2 and vitamin D3)
Vitamin D itself is inactive, it requires modification to the active metabolite, 1,25-dihydroxyvitamin D3. Active vitamin D is not a classic hormone because it is not produced and secreted by an endocrine “gland.” Nor is it a true “vitamin” since it can be synthesized de novo.
However active vitamin D is considered to be a hormone as it acts on distant target cells to evoke responses after binding to high affinity receptors
1,25 hydroxycholecalciferol (calcitriol) increases the activity of both osteoblasts and osteoclasts thereby increasing the rate of bone remodeling, but without a large net effect on the amount of bone present.
Increases GI calcium and phosphate absorption and renal calcium reabsorption - 12Describe the action of Vitamin DVitamin D, after its activation to the hormone 1,25-dihydroxyvitamin D3(calcitriol or 1,25-dihydroxycholecalciferol) is a principal regulator of Ca2+.
1,25-dihydroxyvitamin D3 increases Ca2+ absorption from the intestine and Ca2+ resorption from the bone.
Active vitamin D (or 1,25-dihydroxy vitamin D3 ) is a lipid soluble hormone that binds to a typical nuclear receptor (VDR), analogous to steroid hormones.
Because it is lipid soluble, it travels in the blood bound to hydroxylated a-globulin.
There are many target genes for 1,25-dihydroxy vitamin D3. - 13Describe the effect of Vitamin D on bonesAnother important target for 1,25-dihydroxyvitamin D3 is bone, where it promotes resorption.
Osteoblasts, but not osteoclasts have vitamin D receptors. So is the effect indirect?
1,25-dihydroxyvitamin D3 acts on osteoblasts which produce a paracrine signal that activates osteoclasts to resorb Ca2+ from the bone matrix.
Inadequate supply of vitamin D results in rickets, a disease of bone deformation - 14Describe the intracellular function of calciumNeurotransmitter & hormone release
Muscle contraction
Cell Excitability
-Voltage-Gated Calcium Channels
-Calcium-Dependent Conductances
Synaptic Plasticity
-Long-Term Potentiation
Neurotoxicity
-Ischaemic Brain Damage
Cytoskeletal Changes
Neurite Outgrowth
Protein Synthesis - 15Describe the unique features of the calcium ionSuch diverse cellular functions must reflect certain unique intrinsic features.
It may, for example, be its ionic radius along with the attendant divalent charge.
These features may have allowed biological processes to develop discriminating mechanisms.
The presence of specific Ca transporters means that its cellular concentrations can be very precisely regulated. - 16How does calcium enter a cell?Cells possess at least one, if not two, Ca influx mechanisms
Ca entry via a ligand-gated Ca-channel
Ca leak through passive bilayer diffusion or entry via gap junctions - 17Describe L-type voltage-sensitive Ca channelsstrong depol. current activates,
Ca currents of long duration, inhibited
by Nifedipine. - 18Describe T-type voltage-sensitive Ca channelsWeak depol. current activates,
rapidly inactivated in voltage dependent
manner. Insensitive to inhibitors of L-type. - 19Describe N-type voltage-sensitive Ca channelsN-Type - Require strong depol. current
for activation. Inactivation moderately
rapid. Insensitive to DHP inhibitors but not to conotoxin - 20Describe P-type voltage-sensitive Ca channelsP-Type - Medium depol. current activates
not inhibited by DHP inhibitors or conotxin but sensitive to funnel web Spider Toxin - 21Describe receptor activated Ca-influxNot dependent on membrane depolarization but may be:
A channel that is activated in response to an intracellular
messenger such as an inositol phospholipid (IP4)
or perhaps by Ca itself.
A channel activated in response to interaction with a G-protein.
A receptor which upon binding agonist conducts Ca like the Ach
receptor - binding of Ach causes Na inflow. - 22What are the two mechanisms by which calcium efflux can occur?ATP-driven Ca-ATPase
Na/Ca exchange - 23Describe the Na/Ca exchangeFacilitates rapid outflow of Ca that
has entered through voltage-gated
Ca channels.
3 x 109 Ca ions may be shifted/
second via this mechanism.
Charge imbalance - thus process
is electrogenic and can be
influenced by membrane potential.
Energy provided by Na gradient. - 24Describe the Ca-ATPase~ 140 kDa PM-bound protein.
Electroneutral transfer 2H for 2Ca.
Extrudes Ca against a gradient therefore requires energy input.
Calmodulin enhances affinity and rate of Ca pumping.
Ca-ATPase functions to maintain basal intracellular [Ca] over prolonged periods - 25Describe Ca-binding proteinsBind Ca and thus contribute
to the Ca-buffering capacity
e.g. Calbindin, Calretinin and paralbumin - 26Describe Ca-modulated proteinsThe activity of these proteins
is directly affected by changes
in cytosolic [Ca]. - 27What are the 2 classes of Ca modulated proteins?Those with helix-loop-helix (HLH) structures of oligomeric proteins including calmodulin, troponin C, S100 proteins, calpain
Non HLH proteins including protein kinase C, annexins, Ca-activated ion channels - 28Describe the HLH structure12 amino acid residues
flanked on either side
by a helical arrangement
Calmodulin has 4
HLH motifs allowing 4 Ca
ions to be bound per molecule - 29What is it about the HLH site that allows high affinity Ca binding?Perhaps affinity is related to the 2 positive charges on the ion and its unique ionic radius
Binding site may not accommodate monovalent ions owing to charges in pocket.
Other divalent ions may not have full access owing to their radius and cannot make the appropriate charge contact - 30What biological processes are affected by Ca-modulated proteins?Activation of Ca-sensitive Adenylate Cyclase
Calmodulin-activated phosphodiesterase - expressed in tissues not expressing Ca-sensitive cyclase
Troponin C and skeletal muscle contraction
Phosphorylase kinase (PK) is a Ca-dependent kinase – converts phosphorylase inactive b-form to active a-form. - 31Describe phospholipase CResponsible for initiating PI hydrolysis.
Cytosolic and membrane bound forms - latter probably more important owing to close substrate proximity.
6 types of phospholipase C identified (β, γ, δ, ε, ζ, η) & classified according to structure and regulatory domains...each type has subtypes, for example PLC-B1, PLC-B2 types differ in their ability to hydrolyze PI, PIP or PIP2 and their dependence on Ca2+ and Rho/Ras (PLC epsilon)
PLC substrate specificity variable in vitro - may depend on prevailing cytosolic Ca concentration. - 32How is PLC regulated by its substrates?Regulation of PLC activity by substrates
Large amounts of phosphatidylcholine inhibit PLC
Phosphatidylserine and DAG oppose this effect. Altered activity thought to be due to change in enzyme conformation which affects substrate hydrolysis - 33How is PLC regulated by its G proteins?In some cells (neutrophils and mast cells) pertussis toxin, which ADP-ribosylates Gi, inhibits PLC activity
Addition of GTPS, a non-hydrolysable GTP analogue, to membrane preparations results in PLC activation - 34How does IP3 affect intracellular Ca pools?In non contracting cells mitochondria is one of the major stores of Ca.
However, use of permeable cell preparations led to the finding that there was a second, low capacity, but high affinity pool of labile Ca.
This pool was discriminated from the mitochondria because inhibitors such as oligomycin and rotenone did not prevent agonist mediated Ca release.
This second pool was a vesicular compartment that took up Ca in an ATP-dependent manner and stored Ca could be released by Ca ionophores such as ionomycin and A23187. This pool was the ER. - 35What is the action of IP3 and IP4?IP3 - Can either be broken down to yield inositol or it can be phosphorylated to IP4
IP4 - Has 2 fates can either be degraded to inositol or may fulfil some 2nd messenger function - 36How does Diacylglycerol (DAG) act as a secondary messenger?Protein kinase C (PKC) activity is dramatically activated by DAG in the presence of physiological [Ca] in the 0.1 - 1uM range
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- Regulatory physiology and pharmacology Fichas sobre Calcium, creado por Megan MacLeod el 16/06/2019.
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- Megan MacLeod
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