Download Thyroid Endocrinology

Thyroid Endocrinology
Chapter 9 in Randall et al. “Eckert Animal Physiology”
Chapters 4 & 13 in Hadley “Endocrinology”
Chapters 2 & 14 in Hill et al., “Animal Physiology”
Chapters 2, 7 & 8 in Norris “Vertebrate Endocrinology”
Major concepts covered in thyroid section:
— Negative feedback regulation of hypothalamus-pituitary
hormone secretion
— Positive feedback actions of hormone
— Multi-hormonal interactions in controlling a biological
response
— Local “non-endocrine” as well as endocrine regulation of
hormone release
— Parallel mechanisms of actions of thyroid hormones and
steroid hormones (intracellular receptors)
— General mechanisms of nuclear receptors and receptor
action
— Local activation of circulating hormones, another
concept of “prohormone”
— Plasma binding proteins for hormones
Some major functions of thyroid hormones in mammals
— decrease cholesterol level in plasma
— affect development of the nervous system, increase myelination
— increase brain activity
— increase glucose absorption by gut
— increase basal metabolic rate and O2 consumption
— increase heart rate
— potentiates the action of growth hormone (permissive action of
thyroid hormone)
— other growth and differentiation effects
Some major functions of thyroid hormones in lower
vertebrates
— promotes growth and protein synthesis
— influences food conversion in somatic growth
— stimulates molting in snake and growth of feathers in birds
(epidermal action)
— stimulates parr-smolt transformation in salmonids and
metamorphosis in amphibians
Several major kinds of thyroid hormones
(all are iodinated thyronines or conjugated tyrosines)
OH
I
I
I
I
O
I
OH
OH
O
O
I
I
I
I
I
CH2
CH2
CH2
CH
CH
CH
COOH NH2
Thyroxine , T4
(tetraiodothyronine)
(Major form released)
COOH NH2
3,5,3’-triiodothyronine, T3
(More active than T4)
COOH NH2
3,3’,5’-triiodothyronine, rT3
(reverse T3, inactive form)
Thyroid tissue - thyroid follicle
Thyroid
Basic unit for thyroid tissue - thyroid follicle
Thyroid follicular cells
(produces thyroid hormone
and its precursor protein)
Blood capillary
Thyroid colloid
(containing precursor
protein that can form
thyroid hormones)
Basic unit for thyroid tissue - thyroid follicle
“Active” - thick columnar
epithelium, colloid vacuolated
“Inactive” - thin cuboidal
epithelium, colloid “full”
Thyroid gland of mammals contains several endocrine tissues
— Thyroid follicles (produces thyroid hormones)
— C-cells (produces calcitonin)
— Parathyroid (produces parathyroid hormone)
— Another example of a gland with multiple endocrine secretions
(— Why this kind of association?)
Origin of Thyroid Gland
— Thyroid hormone is the only iodine-containing hormone
— Iodine concentrating cells are found even in invertebrates but
most of these are cells exposed to the external environment
— Vertebrate thyroid develops as an evagination of the floor of
the oral epithelium behind the oral plate (thyroid
diverticulum)
— Subpharyngeal gland in larvel lamprey concentrates iodine
and produces iodine-containing proteins and is open to the
oral cavity via the subpharyngeal duct
— Thyroid hormones might have originated as compounds
released into the gut and then subsequently used as a
hormone
Thyroid Hormone Synthesis and Release (1)
1) thyroglobulin has to be synthesized
OH
OH
tyrosines on
thyroglobulin
CH2
CH2
CH
CH
Thyroid Hormone Synthesis and Release (2)
Synthesis of iodinated thyronine via thyroid peroxidase action
1) thyroglobulin has to be synthesized
4) Storage of iodinated thyroglobulin
in the colloid
OH
OH
tyrosines on
thyroglobulin
CH2
CH2
CH
CH
Thyroid
peroxidase
2) Iodination of
tyrosine residues
(organification
of iodine e.g., forming DIT)
I
I
I
CH2
CH2
CH
CH
OH
I
I
O
I
OH
OH
I
3) Conjugation of iodinated
tyrosine residues to
form iodinated thyronine
(coupling reaction)
Example shows two DIT
conjugating to form
tetraiodothyronine.
Thyroid
peroxidase
I
CH2
CH
Iodinated thyroglobulin
Thyroid Hormone Synthesis and Release (3)
Stored iodinated thyroglobulin in colloid
OH
I
Reabsorption of colloid by phagocytotic
Action of thyroid epithelial cells
I
I
Enzymatic processing of reabsorbed
thyroglobulin in thyroid epithelial cells
+
O
I
CH2
Fragments of
thyroglobulin
CH
COOH NH2
Thyroxine , T4
(tetraiodothyronine)
Fragments
recycled
T4 can be released
Thyroid Hormone Synthesis and Release (4)
— Several potential forms of iodinated thyronine can be
synthesized in the thyroid
— This depends on the conjugation of iodinated tyrosines
on the thyroglobulin molecule
DIT + DIT
T4
MIT + DIT
T3 or reverse T3 (3,3’,5’-triiodothyronine)
MIT + MIT
MIT + T
DIT + T
T2 forms
T1 forms
T2 forms
Neuroendocrine Control of Thyroid Gland Activity
External & Internal Influences
Long-loop -ve feedback
(–)
Brain
Hypothalamus
TRH
(+)
(–)
DA
(–)
Pituitary
thyrotropes
(+)
TSH
Thyroid
Action on
Target cell
T4 and T3
BLOOD or
TISSUE
FLUID
TSH
Na+/K+ ATPase
TSH
receptor
Na+
ATP
Pentose PO4
Pathway
Peroxide
vesicular transport
of Tg to colloid
Amino acids
recycling
Degradation of
Tg in lysosome
I-
cAMP/PKA
Thyroglobulin
(Tg) synthesis
Free T4
(& T3)
Na+/I- cotransport
Tg
MIT DIT &
Tg fragments
I I
Tg
Recycling of
Free I
Pinocytosis &
reuptake of colloid
Iodothyronines
In Tg in colloid
Thyroid Follicular
Epithelial Cells
Release of
T4 & T3
by diffusion
COLLOID
SPACE
TSH ACTION
ON THYROID
Na+
I I
Tg
Membrane Thyroid
Peroxidase Activity
Iodination of tyrosine &
formation of iodothyronines
Changes in Thyroid Hormone Regulation During
Metamorphosis in Frogs
T3/T4
TSH
Acquisition of
hypothalamic
sensitivity to +ve
feedback by
thyroid hormones
Premetamorhposis
TRH
Prometamorphosis
Resumption of -ve
feedback regulation
by thyroid hormones
Climax
Postmetamorphosis
Stages of amphibian development
Neuroendocrine Control of Thyroid Gland Activity Just Prior
To and At Metamorphosis in Amphibians
External & Internal Influences
Long-loop +ve feedback
(+)
Action on
Target cell
E.g., gill & tail
reabsorption
Brain
Hypothalamus
TRH
(+)
(+)
DA
(–)
Pituitary
thyrotropes
(+)
TSH
Thyroid
T4 and T3
Further Processing of Thyroxine Once Released from Thyroid
OH
I
I
Outer Ring
Deiodination
Outer Ring
3,5,3'-triiodotyronine, T3
(more active hormone)
Deiodinase I & II
(Type I - liver, thyroid & kidney;
II- brain, pituitary, placenta, BAT)
O
I
I
Inner Ring
Deiodination
Inner Ring
CH 2
CH
COOH NH 2
Thyroxine T4
Deiodinase III
Other
metabolites
3,3',5'-triiodotyronine,
rT3,reverse T3
(inactive hormone form)
Schematic of Nuclear Receptor Domains and Functions
Hinge
Hsp90-binding
Leucine-rich Heptads
Zinc-Fingers
Hormone-Binding
DNA-Binding
NH2
A&B
Transactivation
Nuclear localization
signal
Dimerization
Basal Phosphorylation
COOH
C
D
E
F
Nuclear Receptors Superfamily
— includes receptors for steroids, thyroid hormones, vitamins,
xenobiotics, and other “orphaned receptors”
— these are intracellular phosphoproteins
— these are DNA-binding transcription factors
— DNA-binding is achieved through zinc-fingers
Hypothetic DNA-binding zinc-finger
(modified from Bolander:
“Molecular Endocrinology”)
Zn2+
— although nuclear receptors mediate the action of membrane
permeant steroid and thyroid hormones, these hormones are
also known to bind to membrane receptors
Idealized Hormone-responsive elements (HREs) as two half-sites
(Consensus sequences; directionality indicated by arrows)
GRE
(Glucocorticoid)
ERE
(Estrogen)
TRE
(Thyroid Hormone)
DR+3(VDRE)
(Vitamin D3)
A G A A C A n n n T G T T C T
T C T T G T n n n A C A A G A
A G G T C A n n n T G A C C T
T C C A G T n n n A C T G G A
A G G T C A
T C C A G T
T G A C C T
A C T G G A
A G G T C A n n n
T C C A G T n n n
A G G T C A
T C C A G T
Schematic of steroid hormone receptor action on transcription
C
horm
horm
+
horm
horm
change in conformation and
DNA-independent phosphorylation
+
C
C
C
horm
Receptor dimerization via Leu-rich region
horm
C
HRE
C
HRE
DNA binding &
DNA-dependent
hyperphosphorylation
target gene
Stabilization of receptor dimer and DNA binding
Recruitment of adaptor proteins and interactions with nuclear transcription factors
and transcription activators/regulators elements
Regulation of gene transcription
Thyroid Hormone in Circulation & Mechanisms of Action
BP
Plasma binding protein
RA
Retinoids
Thyroid hormone receptor
Retinoid receptor
BP
T4
BP
T4
BP
T3
Target Cell
Nucleus
T3
T3
T3
DII
DI
T4
legend
T3 RA
Transcription
Regulation
RNA
T4
protein
T3 T3
mRNA
Biological Effects
Note 1:
— isoforms of nuclear receptors also present, e.g., TRα and
TRβ
— tissue selective expression of receptor isoforms observed
(e.g., heart expresses more TRα while liver expresses more
TRβ)
— active selectivity may also result from this
Note 2:
— TR and RXR are also located in the mitochondria
— some effects on mitochondrial DNA can also be exerted via
these receptors
— not all effects of TH on mitochondria are necessarily
mediated by “mitochondria genomic action”
Membrane Receptors for thyroid hormones
— the presence of a modified nTR on plasma membrane has not
been shown but thyroid hormones are also known to activate
PLC via membrane actions
— around 2002-2003, evidence suggest that TH can bind to
integrin αVβ3 which can activate PLC
— this “receptor” is characterized by the ability to bind
TETRAC which acts here as an antagonist to block the
actions of thyroid hormones on membrane ion fluxes
Non-endocrine Regulators of Thyroid Activity
— iodine availability in food
— insufficient iodine - TSH-induced hypertrophy and goiter
— great excess of iodine - poisoning of the peroxidase enzyme
— inhibitors of iodine uptake
— thiocyanate - cabbage, Brussels sprouts, turnips, broccoli
etc. contain thioglucosides which form thiocyanates upon
digestion
— other small negatively charged molecules can also compete
for the uptake pump
— other thio-compounds also inhibit the peroxidase enzyme