Endocrine Signalling 1 Flashcards
What do ligands do
Switch on nuclear receptors
What is similar in the structure of ligands
Have aromatic rings
What’s the purpose of these aromatic rings found in ligands
Lipid-soluble - so can enter the cell through the plasma membrane and act on site, might also need to go through the nucleus
What imaging is used to look at endocrine signalling
X-ray Crystallography
What are the three types of negative feedback loops
Long feedback
Short feedback
Ultra short
What happens with the hormone cascade regarding the amount of factor
The concentration of release gets larger -
Neurotransmitter to environmental change (nG)
Hypothalamus releasing hormone (nG)
anterior pituitary trophic hormones (microgram)
Hormone (milligram)
Effect
What is the structure on what steroid hormones are built
CCCP nucleus - cyclopentanoperhydrophenanthrene (sterane)
Also known as cholesterol
How are different steroid hormones structured?
All have CCCP but have extra groups added to make different hormones - oestrogen, progesterone, cortisol etc
How are steroid hormones formation triggered extracellularly
Ligand binds to its g-protein receptor which triggers -
Calcium is released from the endoplasmic reticulum to increase calcium levels in the cell
cAMP release
How are steroid hormones formed
The cell has a lipoprotein receptor that activates cholesterol ester droplets in the cell.
These cholesterol esters enter the mitochondria and start to be made into cortisol
StAR protein is needed to get the cholesterol ester into the mitochondria
Found mostly in mitochondria and endoplasmic reticulum
How are steroid hormones broken down
Difficult as no structure in the body is able to break down CCCP therefore it is made more water-soluble for renal excretion
Makes more water-soluble by adding hydroxy or keto groups
What generates thyroid hormones
Amino acids - tyrosine and iodine atoms attached (T3 and T4)
How do thyroid hormones trigger intracellular processes
Bind extracellularly to G protein-coupled receptor.
What is the essential enzyme for thyroid hormone formation
thyroperoxidase - takes iodide ion to form iodine and then attach them to tyrosine to make MIT or DIT
DIT X2 - T4
DIT +MIT - T3
What is important about thyroid hormones regarding their formation
The way round they’re joined (DIT/MIT) determines if they’re active or not
Where is tyrosine found
In thyroglobulin vesicles - strong oxidase reactions to get out of these vesicles
Give the underlying process for T3 and T4 formation
Strong oxidative reaction to getting tyrosine out of these vesicles.
This is the reason that this happens outside the thyroid cell then renters via endocytosis and cleaved by proteases to release T3 and T4 in the bloodstream. This is to
What is deiodination
Removal of iodine atoms.
Can activate (T4 –> T3) - T3 is more active than T4
Can deactivate - T2 or T1
How do steroid hormones activate their specific nuclear receptors
Steroid enters cell from blood and gets through due to lipophilic.
In the cytoplasm, steroid hormone receptors are present waiting for the ligand to arrive.
They are held in place by shaperones and the ligand binds to receptor and activates it.
The receptor enters the nucleus and binds to DNA, acting as a transcription factor to promote transcription of mRNAs
These mRNAs are translated into protein at the ribosomes.
How do non-steroid hormones activate their specific nuclear receptors
These hormone receptors are already in the nucleus, waiting for the non-steroid hormone to enter the cell followed by the nucleus
The receptor binds to DNA, acting as a transcription factor to promote transcription of mRNAs
These mRNAs are translated into protein at the ribosomes.
What is the 3 important structures of nuclear receptors
Ligand binding domain
DNA binding domain
Unique N-terminal domain (NTD)
What 3 processes do nuclear receptors do
Dimerization
Interaction with chaperones (getting in and out of nucleus)
Interaction with co-regulators (other proteins for transcription factor role)
These can be manipulated with phosphorylation or other groups
What is the function of the ligand binding domain
Forms a ligand-binding pocket that restricts what can bind
What is the function of the DNA binding domain
has 8 cysteine residues which form zinc fingers which are needed for binding the nuclear receptor to the DNA
It also has C-terminal extension which binds to DNA too
What is the function of the Unique N-terminal domain (NTD
- most variable section of many AA. Has an area called the activation function 1 (AF1). Vital for it to work as a transcription factor. The hinge region is a flexible region which is used to change the shape of the protein to expose previously unexposed amino acids and change their function.
(e.g. bind the ligand)
What facilitates the uptake of the steroid hormone into the nucleus once bound to its receptor in the cytoplasm
WIDER READING - Mahato et al (1999)
Nuclear localization sequence - amino acid sequence that tags a protein to allow it to be taken into the cell nucleus by nuclear transport.
Different nuclear receptors can share the same NLS.
What binds to hormone receptors while no hormone is present
WIDER READING - Walter S, Buchner J (April 2002)
Heat shock proteins
What are the two main forms of nuclear receptor protein
WIDER READING - Novac N, Heinzel T (Dec 2004).
Type 1 - HSP binds and found in cytoplasm
Type 2 - no HSP and found in the nucleus
What are the non-genomic effects of steroid hormone binding and give an example
WIDER READING - Luconi 2004
Showed changes in human sperm as a result of oestrogen and progesterone which were too quick to be genetic transcirption and translation -
Changes seen - calcium influx, tyrosine phosphorylation, cAMP increase, hyperactive motilty.
Done western blot analysis to identify mPR and mER on sperm which are allowing progesterone and oestrogen to bind and cause these rapid effects.
How many nuclear receptors do humans have
WIDER READING - Zhang et al 2004
48, 24 of which are transcription dependent factors.
Give some examples of type 1 receptors
WIDER READING - Linja 2004
Glucocorticoid receptor
Progesterone receptor
Androgen receptor
Estrogen receptor
What is the difference about the receptor type 1 and 2 structure
WIDER READING - Amoutzias et al 2007
Type 1 - homodimers
Type 2 Hetrodimers
Give some examples of type II nuclear receptors
Wider reading - Klinge 1997
Retinoic acid receptor
Retinoid X receptor Thyroid hormone
What do coactivators contain and how do they work
WIDER READING - sterner 2000
Agonist ligands bind causing a conformational change in the receptor to form coactivator proteins - contains an intrinsic histone acetyltransferase which weakens histone-DNA associated which promotes gene transcription
What do corepressors contain and how do they work
Wider reading - seo-hee you 2013
An antagonist ligand binds which causes a conformational change in the receptor which makes it more likely that corepressor proteins will bind. When they bind, these proteins recruit histone deacetalyases which strengthen DNA-histone association which stops gene trasncription.
Name two important enzymes for steroid formation
WIDER READING
- Schiffer 2019
Two major enzymes involved are cytochrome P450 and hydroxysteroid dehydrogenase.
What is the free hormone hypothesis
WIDER READING - Mendel 1989
Hormone is only biologically active if unbound from a protein in the plasma.
How are steroid hormones believed to take in sex hormones
WIDER READING - Hammes 2005
Steroid binds to megalin (membrane receptor) and enters the cell via endocytosis where this complex goes to the lysosome and is degraded to leave the steroid to go into the cytoplasm and bind to its target receptor.
How are peptide hormones synthesized
WIDER READING - Bowen 2019
Via the endoplasmic reticulum where they are transferred to the golgi apparatus and put into secretory vesicles for exocytosis. From this they can be excreted by 1 of these pathways -
Regulated secretion
Constitutive secretion
What is regulated secretion
WIDER READING - Bowen 2019
Peptide hormone released in burst from vesicles when stimulated. Most common.
What is constitutive secretion
WIDER READING - Bowen 2019
Continually secreted as it is synthesized
What is the rate limiting step of all steroid hormones
WIDER READING - Bowen 2019
Cholesterol to pregnenolone (formed in mitochondria)
What is the only nuclear receptor and ligand structure that has been structurally solved
WIDER READING - Helsen 2012
Retinoid receptor
What did this study show regarding the structure of the androgen receptor
WIDER READING - Helsen 2012
Mutations occurred in the ligand binding domain and DNA binding domain separately, they had effects on each others binding capabilities but not their own, showing that the areas of mutation are key for communication between each of the two binding domains. These mutations were associated with androgen insensitivity therefore may represent some of the genetic background for this syndrome.
