Please wait while the transcript is being prepared...
0:00
Welcome everyone to Chapter 9 of
this short talk series on
nuclear receptors as
therapeutic targets.
Now after the general part on
the features and mechanisms
of nuclear receptors,
we will now look at the
individual subfamilies and
receptors of this family and
at their functions
and their ligands.
0:21
We will go through
the nuclear receptors
systematically, family
by family, and we start
in this Chapter 9 with
the thyroid hormone receptors
which are the NR1A family.
There are two thyroid
hormone receptor isoforms,
THR Alpha and THR Beta.
As the name indicates,
thyroid hormones are
the natural ligands
of the thyroid
hormone receptors.
0:47
They are produced
in the colloid of
the thyroid gland
by iodination of
tyrosine residues in the
protein thyroglobulin,
and after generation of
mono- and diiodotyrosine
residues in thyroglobulin,
two such residues are fused
to the thyroid hormones by
the enzymatic activity
of thyroid peroxidase.
The processed thyroglobulin
is then taken
up into the thyrocytes
and the proteolysis
releases the free thyroid
hormones; levothyroxine
and triiodothyronine
abbreviated as T4 and T3
according to the number of
contained iodine atoms.
1:29
The thyroid hormone
system is regulated
by the thyrotropin-releasing
hormone,
which is released from the
hypothalamus and then stimulates
the pituitary gland to
release the
thyroid-stimulating hormone,
abbreviated as TSH,
and also known as thyrotropin,
which, in turn, then stimulates
the thyroid gland to
produce T4 and T3.
T3 and T4, in turn,
block TRH and TSH release
in the hypothalamus and
the pituitary gland and thus,
regulate their own levels in
a negative feedback mechanism.
T4 and T3 are produced in
the thyroid gland
and released to
the circulation approximately
in a 14-1 ratio.
However, T3 is more active as
hormone and thyroid hormone
receptor agonist, by 3-44.
Therefore, T4 is deiodinated in
the peripheral organs
to T3 by deiodinases,
and further deiodination then
inactivates the hormone.
Three activates the
thyroid hormone receptors,
which form heterodimers
with RXR and
RDNA bound also in the
absence of their ligand.
In absence of T3,
the thyroid hormone receptor,
RXR dimer, recruits
an co-repressor complex and
thus, suppresses
gene expression,
as shown here on
the upper right.
T3 binding induces
the release of
the co-repressor complex
and the recruitment of
a co-activator
complex to activate
expression of thyroid hormone
receptor-regulated genes.
By this mechanism,
thyroid hormones regulate
the metabolism of almost
every tissue in the body.
