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In
addition, if hypocalcemia persists, there is an increase not only in
the secretion, but also in the formation of the hormone and in cellular
proliferation, with a hyperplasia of the parathyroid glands.
The
"sensor" in charge of measuring extracellular levels of calcium and
of transmitting the signal to the parathyroid cells is a membrane receptor
(CaR). High concentrations of extracellular calcium mediate the inhibition
of PTH secretion by activating the CaR situated on the plasmatic membrane
of the parathyroid cells.
The
calcium receptor situated on parathyroid cells represents an essential
molecular entity for the regulation of the systemic homeostatis of calcium,
even though the mechanism by means of which the calcium receptor inhibits
rather than stimulating PTH secretions has not yet been explained.
The key role played by CaR is testified by two types of demonstration,
one based on molecular genetics' data and the other one on pharmacological
data. In fact, certain genetic diseases associated with an altered systemic
homeostatis of the calcium ion, are caused by CaR changes.
Furthermore,
selective cal-cium-mimetic compounds (CaR activat-ors) lower the serum
levels of PTH and of calcium ion in hyperparathyroid patients. CaR is
also involved in the regulation of the long-term responses of parathyroid
cells, such as PTH sysnthe-sis and cellular proliferation.
The
marked hyperplasia of chief cells, both in patients affected by severe
neonatal hyper-parathyroidism - leading to inactivating changes of the
CaR gene in homo-zygosis - and in "knockout" mice due to the CaR gene,
is a demonstration of the role played by CaR in the suppression of parathyroid
cells' proliferation.
3.
Biologic effects of PTH PTH acts directly on the bone, by stimulating
its re-absorption and the discharge of calcium into the extra-cellular
liquid (Picture 4).
The response of the bone to the action of PTH is slow and is the result
of a complex cascade of intra- and inter-cellular regulating events
with a finale effect leading to a loss in osseous mass owing to the
activation of the cells in charge of osseous re-absorption (picture
5).
In the kidney, PTH acts rapidly by increasing phos-phate excretion and
calcium re-absor-ption. PTH also indirectly increases intestinal absorption
of calcium taken in with food, by stimulating in the kidneys the 25-idroxy-vitamin
D3-1a-idroxylase, which causes the transformation of 25(OH)D into 1,25(OH)2D3,
the active metabolite of vitamin D3.
The active hormone acts in the intestine by stimulating the activity
of a calcium-binding protein and by facilitating the conveyance, both
of calcium and phosphates, from the intestinal lumen to the bloodstream.
The
action of PTH on the kidneys, on the bones and on the intestine increases
the calcium flow towards the extracellular liquid and safeguards the
body from hypocalcemia.
The
biological effects of PTH, as those of other peptidic hormones, are
mediated by the binding of the hormone with a specific receptor situated
on the plasmatic membrane of the cells of the target tissues.
This
interaction results in the production of a second messenger which starts
up a sequence of metabolic events.
The
typical second messenger produced by the biological effects of PTH is
the intracellular cyclic AMP (cAMP).
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