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Calcium as a Regulatory and
Signaling ion
Chiranjeevi Kumar
Tutor/Demonstrator
Dept of Physiology
AIIMS Bhopal

 Calcium facts
 Calcium history
 Plasma calcium levels
 Cellular Distribution
 Ca2+ channels

 Ca2+ binding proteins
 Role of calcium as a regulatory and signaling ion
 Calcium homeostatsis
 Research on Calcium
 Applied aspects

 Summary

Calcium facts
 2% of body weight
 99% in bones
 1% in body fluids
 Soft grey alkaline earth metal

 Occurs naturally in limestone, gypsum, and fluorite
 Symbol Ca & Single oxidation state +2
 Atomic Number 20 & Atomic weight 40 g/mol
 Group II element in Periodic table
 Divalent cation

 Fifth most abundant element in Earth´s crust & Essential for life
...
He is best remembered today for his discoveries of
several alkali and alkaline earth metals as well as contributions to the discoveries of
the elemental nature of chlorine and iodine
...

 Calcium in plasma or serum exists in three forms or fractions:
 1) Protein-bound calcium
 2) Ionized or free calcium
 3) Complexed or chelated calcium
Protein-bound calcium cannot
diffuse through membranes
and thus is not usable by
tissues
Ionized or free calcium is the
physiologically active form
Complexed or chelated calcium
is bound to phosphate,
bicarbonate, sulfate, citrate,
and lactate

Cellular Distribution
Ionic cytosol Ca is maintained at about
10-7 molar
...

Therefore, the major threat to cell
viability is excessive Ca influx from the
extracellular space along the
electrochemical gradients
...

 Calcium channels opened after ligand binding to the receptor (e
...

glutamate/NMDA receptor;ATP receptor; nicotinic ACh receptors ;
prostaglandin receptors
 Voltage gated
...

 Long-lasting
...

 Activated by emptying of intracellular stores, exact mechanism unknown

Type

Properties

Location/Function

Blockers

L

High activation
threshold;
slow inactivation

Plasma membrane of many
cells;
main Ca++ source for
contraction in
smooth and cardiac muscle

Dihydropyridine;
verapamil;
diltiazem

N

Low activation
threshold;
slow inactivation

Main Ca++ source for
neurotransmitter
release by nerve terminals

ω-Conotoxin
(snail venom)

T

Low activation
threshold;
fast inactivation

Widely distributed; important Mibefradil;
in cardiac pacemaker and
(verapamil;
Purkinje
diltiazem)
cells

Ca2+ binding proteins
• Troponin
...

• Calbindin
...

• Phospholiphase A2
...

• Calsequestrin
...


Role of calcium as a regulatory and signaling ion
 In Learning and memory
...

 In fertilization
 In immune response
 In Gene regulation
 In Cell injury
 In Modulation of ion channel activity
 In visual adaptation

Formation of bones and teeth
Calcium is a major structural element in
bones and teeth
...

This complex provides the hard and rigid
structure of bone which is essential to its
function
...


Calcium As A Cofactor For Many Enzymes
Protein kinases (PKs)
are the effectors of
phosphorylation

is a phosphotransferase enzyme that
catalyzes the interconversion of adenine
nucleotides, and plays an important role in
cellular energy homeostasis
...
NO is an
important cellular signaling molecule
...

Synthesis of these Gla residues results from post-translational
modifications of the newly synthesized factors in the liver
endoplasmic reticulum by a vitamin K
This amino acid is a natural high affinity binder (or chelator)
of calcium ions, hence the designation of calcium as a cofactor in the blood clotting cascade
...


Role of calcium In the constriction and relaxation of
blood vessels

• Contraction in VSM can be initiated by
Passive stretching of VSM can cause contraction that originates from
the smooth muscle itself and is termed as a myogenic response
Electrical depolarization of the VSM cell membrane also
elicits contraction, most likely by opening voltage
dependent calcium channels (L-type calcium channels)
chemical stimuli such as norepinephrin, vasopressin, endothelin-1,
angiotenisin 2 and thromboxane A2 can cause contraction
The mechanism of contraction involves different signal transduction pathways,
all of which converge to increase intracellular calcium
...

1) reduced release of calcium by the SR or reduced calcium entry into the cell,
2) inhibition of MLCK by increased intracellular concentration of cAMP, and
3) phosphatase-activated MLC dephosphorylation
...

Although the physiological role of calpains is still poorly understood
but a transient and localized influx of calcium into the cell activates a
small local population of calpains close to Ca2+ channels
These calpains activates signal
transduction pathway and catalyzing the
controlled proteolysis of its target proteins
Calpains
have been implicated
in apoptotic cell death, and appear to be
an essential component of necrosis
...
a
...
This brings about contraction in smooth muscle
CaMKI is concerned with synaptic function
CaMKII is concerned with neurotransmitter secretion, transcription
factor regulation & glycogen metabolism
CaMKIII is concerned with protein synthesis
Another calmodulin-activated protein is calcineurin, a phosphatase that
dephosphorylates NFATC
...


Role of Ca2+ in long term potentiation
• LTP relies on calcium influx
at NMDA glutamate receptors
• Calcium channels controlled
by the NMDA receptor are
blocked by a magnesium ion
– Magnesium ion is ejected by:
1
...
depolarization of the postsynaptic cell (by activity at
AMPA receptors on the
membrane)

Role of Ca2+ in long term potentiation

Role of Ca in Skeletal muscle contraction

Role of Ca in Skeletal muscle contraction
Role of Ca in Skeletal muscle contraction

Role of Ca in Skeletal muscle contraction

Relaxation occurs when Ca +2is
reaccumulated in the sarcoplasmic
reticulum by the Ca +2ATPase of
the sarcoplasmic reticulum
membrane ( SERCA )

Role of Ca in Cardiac muscle contraction

Role Ca in smooth muscle contraction
Role of Cain Smooth muscle contraction
Smooth muscle does not contain the
protein troponin;instead calmodulin, cal
desmon and calponin are significant
proteins expressed within smooth
muscle
...

Caldesmon has been suggested to be
involved in tethering actin, myosin and
tropomyosin, and enhance the ability of
smooth muscle to maintain tension
...

At the time of fertilisation sperm delivers phospholipase C into the egg
which triggers a series of Ca2+ spikes lasting several hours

These Ca2+ spikes are necessary for all the events of fertilization, including
exit from metaphase II arrest and extrusion of cortical granules that block
the entry of other sperm
...


Role Of Calcium In Fertilization
To remain in metaphase II, arrested eggs must maintain high levels of
Maturation-Promoting Factor (MPF) activity, a heterodimer of CDK1
and cyclin B1
...


Role of calcium in Immune response
TCR stimulation
[Ca++] increases
Binds to Calmodulin and activates Calcineurin
dephosphorylates NFATc
NFATc translocates to nucleus where it combines with NFATn and induces
transcription of IL-2 gene
T cell proliferation

Calcineurin: target of immunesuppressive drugs FK506 and
cyclosporine, which form a complex with immunophillins and
compete with Ca++/CaM for binding to calcineurin

no NFATc
activation

Role of calcium in Immune response

Role Of Calcium In Gene Expression

Hogan P G et al
...
2003;17:2205-2232

Cold Spring Harbor Laboratory Press

Role Of Calcium In Cell Injury
Causes of Cell Injury
Oxygen Deprivation (Anoxia)

Physical Agents
Chemical Agents
Infections Agents
Immunologic Reactions
Genetic Defects
Nutritional Imbalances

Injury mechanisms
Decreased Atp
Mitochondrial Damage

Increased Intracellular Calcium
Increased Free Radicals
Increased Cell Membrane Permeability

Role of calcium In Modulation of ion channel activity
• Calcium-activated potassium channels are divided into BK channels, IK
channels, and SK channels based on their conductance (big, intermediate,

and small conductance)
...

• Calcium-activated chloride channels (CaCCs) play important roles in
cellular physiology, including
– epithelial secretion of electrolytes and water,
– sensory transduction,
– regulation of neuronal and cardiac excitability, and
– regulation of vascular tone
...


SK channels are activated by an increase in the concentration of intracellular calcium
through N-type calcium channels
...


IK channel

is expressed mainly in peripheral tissues such as those of

the haematopoietic system, colon, placenta, lung andpancreas
...

A K+ channel pore domain (S5,
selectivity filter, and S6)
...
contains four
primary binding sites for Ca2+, called
"calcium bowls"

Role of Ca2+ in visual adaptation
Phototransduction
•Starts with photon absorption by
rhodopsin
•Transducin binds to activated
rhodopsin , exchanges GTP for GDP
•Activated transducin dissociates into
 and  subunits
•The  subunit binds to, and
activates, phosphodiesterase
•Intracellular cGMP concentration
decreases
•Reduction in cGMP closes cGMPgated cation channels in the plasma
membrane

•Membrane potential hyperpolarizes
•Closing of cGMP-gated channel
reduces intracellular calcium
•Reduced calcium counteracts the
effects of light absorption

Role of Ca2+ in visual adaptation

Calcium homeostatsis

Exercise and Calcium
• Normal bone function requires weight-bearing exercise
• Regular physical activity has been associated with many positive
health benefits including strong bones
...

• Weight-bearing physical activities cause muscles and bones to

work against gravity
• Lack of weight-bearing exercise decreases bone formation
• Total bed-rest causes bone loss and negative calcium balance

Research on Calcium
See in particular:
• Calvo MS et al
...
” Nutrition 2000 Vol 16 (7/8)
...
, “ High sodium associated with fast-food consumption
competes for renal reabsorption of calcium and PTH secretion “
• Harland BF et al
...
Nutrition 2000 Vol
16 (7/8)
• Intake of carbonated beverages (soda pop) has been associated with

increased excretion and loss of calcium
• Excessive intake of Na may cause renal hypercalciuria by impairing Ca
reabsorption

Applied aspects
Hypocalcemia
Hypercalcemia
Lambert – Eaton syndrome
COFFIN – LOWRY syndrome (RPS6kA3)

Timothy's syndrome (Long QT syndrome) (LTQ1 – 13)
WOLFRAM syndrome (DIDMOAD)

Toxicology
• The UL for calcium is 1200 - 1500 mg/day
• MAS (Milk alkali syndrome)
- Rare and potentially life threatening condition in individuals
consuming large quantities of calcium and alkali
- Characterized by renal impairment, alkalosis and

hypercalcemia: cause progressive depression of the nervous
system

Final word

A “vital life element”

•Calcium

not to be ignored

A very exciting area
for research

Thank you for your attention

• Rolein surfactant
• Role in peripheral chemoreceptors in chemical
regulation of respiration



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