Download PARATHYROID HORMONE

Parathyroid
Hormone
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Parathyroid Hormone
Important in calcium metabolism
as well as in phosphate
metabolism
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Anatomy of Parathyroid
Glands
Four parathyroid glands in the human
being
Develop at 5 – 14 weeks of gestation
from 3rd and 4th branchial pouches
They descend to lie posterior to the
thyroid gland,
One behind each of the upper and each of
the lower poles of the thyroid
Ectopic locations in the neck and
mediastinum occur
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Anatomy of Parathyroid
Glands
Total wt of adult parathyroid
tissue is about 130mg,
One gland with 30 – 50mg
Their blood supply is from thyroid
arteries
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Anatomy of Parathyroid
Glands
Histological appearance of the
gland changes with age:
The predominant cells (chief cells)
Are present throughout life
Source of PTH
They have abundant glycogen, Golgi
apparatus and few clusters of
secretory granules
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Anatomy of Parathyroid
Glands
Oxyphil cell
• First appears at puberty
• Distinguished by an eosinophilic
cytoplasm
• Believed to be modified or depleted chief
cells that no longer secrete hormone
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Synthesis and Release of
PTH
Synthesized on the ribosomes in the
form of a preprohormone,(preproPTH)
A polypeptide chain of 115AA
Prepro-PTH is transported to ER
Where it is cleaved to a prohormone
with 90AA
A leader sequence containing 25AA
residues is removed from the n-terminal
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Leader sequence
H2N-Met-Met-Ser-----------------------Gly-Lys---Gln-Ser------Phe-Asn--------Val-Ser-Arg----
C-fragment
sequence
Active
sequence
Prepro-PTH
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H2N-Lys------
Gln-Ser------Phe-Asn--------Val-Ser-Arg----
C-fragment
sequence
Active
sequence
Pro-PTH
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Synthesis and Release of
PTH
Pro-PTH is transported to Golgi
apparatus
Additional 6AA residues are
removed
From the n-terminal to form PTH
with 84aa,mw 9500
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H2N-Lys-----
Gln-Ser------Phe-Asn-------Val-Ser-Arg----
C-fragment
sequence
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Active
sequence
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84
1
Gln-Ser------Phe-Asn------------Val-Ser-NH2
C-fragment
sequence
Active
sequence
Parathyroid hormone
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Synthesis and Release of
PTH
Finally packaged in secretory
granules in the cytoplasm of cells
Plasma level of intact PTH is 10-55
pg/ml
Half life of less than 20min
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Synthesis and Release of
PTH
Biological activity resides in the nterminal portion of the molecule within
amino acid 1 – 27
The first 2AA are essential
Cleavage of PTH between AA 33, and 40
also occur
Leading to smaller compounds with as few
as 34AA adjacent to the N- terminus of the
molecule
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PTH Actions
Its paramount effect is to increase
plasma Ca2+ levels by
Stimulating bone resorption
Renal tubular Ca2+ reabsorption
And 1,25 – (OH)2D3 synthesis
PTH decrease plasma phosphate
concentration
By Inhibiting renal tubular phosphate
reabsorption
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Mechanism of PTH
Actions
PTH action is initiated by binding
to a plasma cell membrane
receptor
This is glyprotein composed of
multiple subunits of 85,000mw
The 14 to 34 regions of PTH
contains the binding sequence
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Mechanism of PTH
Actions
Interaction of PTH with receptors
on the surface of target cells
↑ The formation of camp and of
IP3 and DAG
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Mechanism of PTH
Actions
The PTH receptor is coupled to
adenyl cyclase through
stimulatory G proteins (Gs)
And to phospholipase C through
another G protein
Consequently, protein kinase A
and C are activated and
intracellular calcium is increased
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PTH
Phospholipids
Plasma
membrane
Gs protein
PLC
Phosphatidy linositol
Arachidonic acid
DAG
PG’s
Modulate cell
response
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Protein kinase C
activity
or
or
Ca2+
Enzyme activities
Metabolic pathways
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IP3
ER
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PTH
G- Prot Adenyl cyclae
Gs/GI
ATP
cAMP
Prot kinase A
Phosphorylated prot.
Biological effect
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Mechanism of PTH
Actions
Rapid responses almost certainly
result from protein
phosphorylation whereas delayed
responses result from altered
expression of genes
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Effects of PTH:
The overall effect of PTH is
To increase plasma calcium and
decrease plasma phosphate
By acting on 3 major target
organs
• Bone
• Kidney
• GIT
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Calcium and Phosphate
Absorption From the
Bone
PTH accelerates removal of
calcium and phosphate from bone
By 2 phases
• Rapid phase
• Slow phase
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Rapid Phase of Calcium
and Phosphate
Absorption
PTH stimulates osteolysis
Begins in minutes and increases
progressively for several hours
Note: bone fluid&osteocytic
membrane
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Rapid Phase of Calcium
and Phosphate
Absorption
PTH stimulates osteolysis
By increaseing calcium permeability
of the osteocytic membrane
osteolysis occurs without
absorption of bone’s fibrous and
gel matrix
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Slow Phase of Calcium
and Phosphate
Absorption
PTH activates the osteoclasts
Requires several days or even weeks to
become fully developed
It also stimulates the formation of new
osteoclasts
Osteoclasts reabsorb bone itself
Not merely reabsorption of calcium
phosphate salt from the bone
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Slow Phase of Calcium
and Phosphate
Absorption
Osteoclasts do not have
membrane receptor proteins for
PTH
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Slow Phase of Calcium
and Phosphate
Absorption
It is believed that activated
osteoblasts and osteocytes
Send a secondary but unknown
signal to the osteoclasts
Causing them to set their usual task
of bone reabsorption
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Slow Phase of Calcium
and Phosphate
Absorption
After few months, osteoclastic
resorption of bone can lead to
weakened bones and secondary
stimulation of the osteoblasts that
attempt to correct the weakened
state
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Slow Phase of Calcium
and Phosphate
Absorption
PTH also induces increase in acid
Phosphatase and carbonic ahydrase
and accumulates of lactic acid and
citric acid
The resultant lowering of ph
contributes to the resorptive process
PTH also inhibits the synthesis of
collagen by osteoblasts
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Effect of PTH in Kidneys
PTH increase the reabsorption of
calcium from the late distal
tubules, collecting tubules and
early collecting ducts
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Effect of PTH in Kidneys
This effect is mediated by PTH
stimulation of camp production at the
capillary surface of the renal tubular
cell
Absolute amount of calcium excreted in
the urine is elevated in PTH excess
states
Despite an increase in fractional
reabsorption in the tubules
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Effect of PTH in Kidneys
PTH inhibits the reabsorption of
phosphates in the proximal
tubules
PTH also inhibits the reabsorption
of Na+, and HCO3- in the
proximal tubules
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Effect of PTH in Kidneys
PTH stimulate reabsorption of mg2+ by
the renal tubules, also H+
A most important action of PTH in the
kidney
Is to stimulate the synthesis of 1,25-(OH)2D3
Without PTH either none or almost
none of the 1,25(oh)2-d3is formed
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Effects of PTH in GIT
PTH greatly enhances both
calcium and phosphate absorption
from the intestines
By increasing the formation of
1,25(OH)2-D3 in the kidneys
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Effects of PTH in Other
Tissues/organs
Alteration in the function of
CNS,
CVS,
Muscles
Peripheral nerves and of
Other endocrine glands
Are seen in states of PTH excess or
deficiency
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Regulation of PTH
Secretion
The dominant regulator of
parathyroid gland activity is
plasma calcium level
The hormone and the ion form a
negative feedback pair
Secretion of PTH is inversely
related to the plasma [Ca2+] in a
sigmoid fashion
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Regulation of PTH
Secretion
100
0%
2
3
4
5
6
7
Plasma ionized Ca2+ (mg/dl)
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Regulation of PTH
Secretion
Its is actually the ionized fraction
of plasma calcium that regulates
PTH secretion
Suppression of PTH secretion by
calcium
Presents a notable exception to the
usual rule
That calcium influx into endocrine
cells stimulates hormonal secretion
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Regulation of PTH
Secretion
Mechanism
There are plasma membrane protein
receptors for ionized calcium that
responds to changes in ECF [Ca2+]
A low ionized Ca2+ signal is transduced via
a stimulatory Gs protein to adenyl cyclase
The consequent increase in cAMP stimulate
exocytosis of PTH – containing secretory
granules.
Calcium also modulates PTH synthesis and
degradation within the glands
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Regulation of PTH
Secretion
Exposure to a high [Ca2+] for hours to
days depresses the rate of PTH
synthesis by decreasing gene
transcription
Exposure for days to weeks decreases
proliferation of parathyroid cells
Thus elevated calcium levels decrease
PTH synthesis, store, and release as well
as, ultimately parathyroid cell mass
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Regulation of PTH
Secretion
Hypocalcaemia increases PTH
Synthesis, stores, and secretory rate
And ultimately stimulates growth of
the gland
Despite the close physiological
relation of phosphate to calcium,
No direct effect of phosphate on the
parathyroid gland
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Regulation of PTH
Secretion
However a rise in plasma phosphate
does cause a fall in ionized calcium
levels which in turn stimulates PTH
secretion
1,25- (OH)2 D3 inhibits synthesis of
PTH and decrease PTH secretion
Phosphadiesterase inhibitors,
epinephrine,dopamine and histamine
All stimulate PTH secretion
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Regulation of PTH
secretion
 - adrenergic agonists and
prostaglandins
inhibit PTH secretion by decreasing cAMP
levels
Excess Aluminium is also inhibitory
PTH is inherently pulsatile.
In addition there is circadian rhythm with
a nocturnal peak
this rhythm is independent of plasma
Calcium levels
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