Download Regulation of calcium Regulation of calcium

Control of plasma calcium
Regulation of calcium
Systems of the body: Integrative aspects
Helen Christian
normal concentration of plasma calcium
what
h t are the
th effects
ff t off calcium
l i
deficiency
d fi i
&
excess?
what disturbs plasma calcium?
how is calcium ‘sensed’?
the hormones that control the intake and loss of
calcium
consequences of too much/too little endocrine
control
Any questions email:
[email protected]
Extracellular calcium
Is tightly controlled within narrow range to
allow proper functioning of tissues
excitation-contraction coupling
synaptic transmission
platelet aggregation and coaggulation
Total plasma calcium concentration 2.4 mM
Intracellular calcium
Is tightly controlled at levels 10,000 fold lower
than extracellular calcium
Intracellular second messenger in regulation of
cell division
muscle contraction
cell
ll motility
tilit
membrane trafficking
secretion
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Hypocalcaemia
Intracellular calcium
Total plasma calcium concn 2.4 mM
<1.2 mM total plasma
Ca2+ is very dangerous
10-3M
10-7M
causes nerve
hyperexcitability and
muscle tetany
CaBPs
CaBPs
IP3,
IP3
ryanodine
Capacitative
(store-activated)
calcium entry
increases
low sensitivity to Na+
Ca2+
The majority of non-bone calcium is EXTRACELLULAR
Hypercalcaemia
Calcium concentrations
decreased excitability of nerves
Control of plasma & extracellular Ca2+ 1.2
1 2 mM
urinary stones
> 3mM renal failure, 4mM cardiac failure
dangerous in the long term
Total plasma calcium
2.4 mM
50% ionised
45% bound to protein
5% bound to citrate, phosphate
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Effect of protein concentration on
plasma calcium
Loss of protein
in nephrotic
syndrome
i
increases
free
f
Ca2+
45% of ‘normal’ total plasma calcium is
bound to protein
Excess protein in multiple myeloma,
reduces free Ca2+
Effect of phosphate and citrate on
plasma ionised calcium
Effect of pH on plasma ionised calcium
5% of ‘normal’ total plasma calcium is bound to
phophate and citrate
increases the negative charge on plasma proteins
Phosphate: rapid movement of phosphate into
blood, e.g. as a result of crush injury to muscle,
reduces free Ca2+
Alkalosis
more calcium binds to protein, ionised Ca2+ falls
results in hypocalcaemic tetany
Acidosis
decreases negative charge on plasma proteins
Citrate: e.g. from massive blood transfusion reduces
free Ca2+
less calcium binds to protein, ionised Ca2+ rises
results in hypercalcemia
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Total body
calcium
99% is stored in
skeleton
25 Moles, 1kg
1% iin ti
tissues,
circulation
Plasma and bone calcium
homeostasis
Bone
• Bone contains the major store of
body calcium as hydroxyapatite
Ca10(PO4)6 OH2
• Dynamic
D
i ti
tissue
• The bone cells - osteoblasts,
osteocytes, osteoclasts -all play a
role in forming, maintaining and
remodelling bone.
• Mechanical stress stimulates bone
formation, disuse (eg illness; space
flight) causes loss of bone.
Osteoblasts (blue) and osteocytes (green)
maintain bone; Osteoclasts secrete acid and proteolytic
enzymes responsible for breaking down bone
Homeostasis of bone calcium is essential for
bone strength
Homeostasis of plasma ionised calcium (1.2
mM Ca2+) is essential for many vital functions
In normal physiology the demands of plasma
calcium are stronger, bones contain huge
reserves of calcium (approx 1kg)
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Exercise - physical stress on bones
Sensed by osteocytes, bone-lining cells.
Daily requirements for
calcium
Transmit stimulus to osteoblasts via gap junctions
Dietary intake varies enormously, so fluxes
vary
to stimulate new bone synthesis.
•Children, pregnant / lactating women
net accumulation of Ca2+ 3 mmoles/day
•Pubertal growth spurt accumulate
5-7 mmoles/day
•Post-menopausal women and ageing males
Ca2+ loss, osteoporosis
Calcium fluxes
Hormones influencing calcium
Parathyroid hormone
PRINCIPAL CONTROL
Vitamin D and its metabolites
ileum
C l it i
Calcitonin
mmoles
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How and where is Ca2+ sensed?
Parathyroid hormone (PTH)
The calcium sensor/receptor
Principal control of plasma calcium
Secreted in response to fall in serum Ca2+
Restores lo
low plasma Ca2+ to normal
Located in parathyroid gland, kidney distal
tubule gut enterocytes,
tubule,
enterocytes osteoblasts
PTH increases calcium reabsorption in
distal tubule of kidney
Calcium receptor signalling
activated by plasma ionised calcium Æinhibits
adenylate cyclase and stimulates
phospholipase C.
a fall in plasma Ca2+ causes secretion of PTH
Glomerulus
filters ionised and
complexed: 250 mmoles/day
with Na+ + H20
60%
PCT
9%
mainly passive paracellular
reabsorption of 60% with Na
(hormone-insensitive); some
active
DCT & collecting duct
active reabsorption of 9% via
luminal membrane epithelial
Ca channel
Only 1% lost in urine
30%
increases cAMP in distal tubule
epithelia and increases calcium
absorption but not clear which
transporter is affected; stimulates
1α-hydroxylase activity
1%
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Actions of PTH in
bone
PTH
PTH long term actions on bone
acts on osteoblasts in bone
intermittent PTH necessary for normal bone
turnover
rapid: stimulates release of Ca2+ (alters
osteoblasts allowing osteoclast access to osteoid)
long-term: osteoclasts stimulated via osteoblasts
Æbreaking down of bone
Parathyroid hormone summary
released by parathyroid glands when
plasma calcium low
increases
Ca2+
reabsorption in kidney
increases synthesis of 1,25 vitamin D3 in
y
kidney
in bone increases osteoclast activity via
actions on osteoblasts
NFkB
OPGligand = RANK
c-fos
OPG is osteoprotegerin
Pathology of PTH
Deficiency (eg damage in thyroid
g y) or receptor
p
defect (‘PTH
(
surgery)
resistance’)
low plasma Ca2+ - tetany
Excess from parathyroid tumours
b
bone
destruction
d
i
high plasma Ca2+ , urinary stones
sluggish CNS
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Production of Vitamin D and its active
metabolite ‘calcitriol’ 1,25(OH)2 vitamin D3
Vitamin 1,25 D3
Diet
acetate
synthesized
y
in kidney
y in response
p
to PTH
when plasma calcium falls
restores total body calcium and phosphate to
normal
acts to increase:
gut
g
7-dehydrocholesterol
sunlight,
skin
Pre-vitamin D3
calcium uptake from gut
vitamin D3
liver
vitamin D
25-hydroxylase
25 (OH) vitamin D3
calcium reuptake in kidneys
vitamin D3
calcium mobilisation from bone
circulation
Vitamin D Receptor action
VitD R in
i the
th
nucleus bind
DNA and
activate
transcription
kidney PCT
25 vitamin D
1α-hydroxylase
PTH stimulates
1,25 (OH)2 vitamin D3
increases total body calcium
Dietary intake of calcium is primarily
controlled by Vitamin 1,25D3
small intestine absorption controlled by
Vitamin 1,25D3
Acts in enterocytes to increase synthesis of :
Calbindin (calcium shuttling protein)
Ca2+ ATPase (basolateral)
Na+-Ca2+ exchanger (basolateral)
Timescale
- hours
Epithelial Ca2+ channels (apical)
Similar mechanism increases calcium
reabsorption in the kidney
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Vitamin 1,25 D3 stimulates synthesis
of calcium transport proteins
Effects of Vitamin 1,25D3 on bone
Bone
synergises with PTH actions
induces differentiation of
osteoclasts
inhibits osteoblast collagen
g
synthesis
Small intestine, distal tubules kidney
Vitamin 1,25 D3 pathology
Rickets -lack of Vit D3
Vitamin D-resistant rickets
Calcitonin
peptide hormone from C cells in thyroid
Renal rickets
lack of Vit 1,25D3 in renal failure
Adult - osteomalacia
general loss of minerals
Excess 1,25D3
Vitamin D poisoning - renal stones
prevention of hypercalcaemia; excess bone
breakdown
no long term effect on serum Ca2+
effects are over-ridden by PTH if in excess; CT
receptor downregulation
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Raised plasma calcium stimulates
calcitonin release
Calcitonin
Bone
inhibits osteoclast breakdown of bone
greatest effect when resorption rapid
when young
Gut
helps control rise in Ca2+ due to meals
inhibits absorption
Calcitonin pathology
Pathology: no effects
Deficiency: compensated by reduction in
PTH
Sex steroids
Oestrogen and testosterone act on osteoblasts
and precursors.
Deficits lead to osteoporosis
osteoporosis, especially post
postmenopausal.
Excess: secretion by carcinomas
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Osteoporosis
Other hormones
Glucocorticoids
excess causes osteoporosis by
reducing bone protein formation
Thyroid hormone (T3)
excess causes osteoporosis
Insulin, Growth
G
hormone and Insulin-like
growth factors
PTH-related protein
Summary
uncontrolled secretion from some tumours (e.g.
breast, lung, prostate)
acts via PTH receptors on bone and kidney to
increase plasma calcium above normal levels,
known as ‘hypercalcaemia of malignancy’
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