Endocrine Signalling 1

Question 1

What do ligands do

Answer 1

Switch on nuclear receptors

Question 2

What is similar in the structure of ligands

Answer 2

Have aromatic rings

Question 3

What’s the purpose of these aromatic rings found in ligands

Answer 3

Lipid-soluble - so can enter the cell through the plasma membrane and act on site, might also need to go through the nucleus

Question 4

What imaging is used to look at endocrine signalling

Answer 4

X-ray Crystallography

Question 5

What are the three types of negative feedback loops

Answer 5

Long feedback
Short feedback
Ultra short

Question 6

What happens with the hormone cascade regarding the amount of factor

Answer 6

The concentration of release gets larger -
Neurotransmitter to environmental change (nG)
Hypothalamus releasing hormone (nG)
anterior pituitary trophic hormones (microgram)
Hormone (milligram)
Effect

Question 7

What is the structure on what steroid hormones are built

Answer 7

CCCP nucleus - cyclopentanoperhydrophenanthrene (sterane)

Also known as cholesterol

Question 8

How are different steroid hormones structured?

Answer 8

All have CCCP but have extra groups added to make different hormones - oestrogen, progesterone, cortisol etc

Question 9

How are steroid hormones formation triggered extracellularly

Answer 9

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

Question 10

How are steroid hormones formed

Answer 10

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

Question 11

How are steroid hormones broken down

Answer 11

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

Question 12

What generates thyroid hormones

Answer 12

Amino acids - tyrosine and iodine atoms attached (T3 and T4)

Question 13

How do thyroid hormones trigger intracellular processes

Answer 13

Bind extracellularly to G protein-coupled receptor.

Question 14

What is the essential enzyme for thyroid hormone formation

Answer 14

thyroperoxidase - takes iodide ion to form iodine and then attach them to tyrosine to make MIT or DIT

DIT X2 - T4
DIT +MIT - T3

Question 15

What is important about thyroid hormones regarding their formation

Answer 15

The way round they’re joined (DIT/MIT) determines if they’re active or not

Question 16

Where is tyrosine found

Answer 16

In thyroglobulin vesicles - strong oxidase reactions to get out of these vesicles

Question 17

Give the underlying process for T3 and T4 formation

Answer 17

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

Question 18

What is deiodination

Answer 18

Removal of iodine atoms.

Can activate (T4 –> T3) - T3 is more active than T4

Can deactivate - T2 or T1

Question 19

How do steroid hormones activate their specific nuclear receptors

Answer 19

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.

Question 20

How do non-steroid hormones activate their specific nuclear receptors

Answer 20

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.

Question 21

What is the 3 important structures of nuclear receptors

Answer 21

Ligand binding domain

DNA binding domain

Unique N-terminal domain (NTD)

Question 22

What 3 processes do nuclear receptors do

Answer 22

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

Question 23

What is the function of the ligand binding domain

Answer 23

Forms a ligand-binding pocket that restricts what can bind

Question 24

What is the function of the DNA binding domain

Answer 24

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

Question 25

What is the function of the Unique N-terminal domain (NTD

Answer 25

- 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)

Question 26

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)

Answer 26

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.

Question 27

What binds to hormone receptors while no hormone is present WIDER READING - Walter S, Buchner J (April 2002)

Answer 27

Heat shock proteins

Question 28

What are the two main forms of nuclear receptor protein WIDER READING - Novac N, Heinzel T (Dec 2004).

Answer 28

Type 1 - HSP binds and found in cytoplasm Type 2 - no HSP and found in the nucleus

Question 29

What are the non-genomic effects of steroid hormone binding and give an example WIDER READING - Luconi 2004

Answer 29

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.

Question 30

How many nuclear receptors do humans have WIDER READING - Zhang et al 2004

Answer 30

48, 24 of which are transcription dependent factors.

Question 31

Give some examples of type 1 receptors WIDER READING - Linja 2004

Answer 31

Glucocorticoid receptor Progesterone receptor Androgen receptor Estrogen receptor

Question 32

What is the difference about the receptor type 1 and 2 structure WIDER READING - Amoutzias et al 2007

Answer 32

Type 1 - homodimers Type 2 Hetrodimers

Question 33

Give some examples of type II nuclear receptors Wider reading - Klinge 1997

Answer 33

Retinoic acid receptor Retinoid X receptor Thyroid hormone

Question 34

What do coactivators contain and how do they work WIDER READING - sterner 2000

Answer 34

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

Question 35

What do corepressors contain and how do they work Wider reading - seo-hee you 2013

Answer 35

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.

Question 36

Name two important enzymes for steroid formation WIDER READING - Schiffer 2019

Answer 36

Two major enzymes involved are cytochrome P450 and hydroxysteroid dehydrogenase.

Question 37

What is the free hormone hypothesis WIDER READING - Mendel 1989

Answer 37

Hormone is only biologically active if unbound from a protein in the plasma.

Question 38

How are steroid hormones believed to take in sex hormones WIDER READING - Hammes 2005

Answer 38

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.

Question 39

How are peptide hormones synthesized WIDER READING - Bowen 2019

Answer 39

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

Question 40

What is regulated secretion WIDER READING - Bowen 2019

Answer 40

Peptide hormone released in burst from vesicles when stimulated. Most common.

Question 41

What is constitutive secretion WIDER READING - Bowen 2019

Answer 41

Continually secreted as it is synthesized

Question 42

What is the rate limiting step of all steroid hormones WIDER READING - Bowen 2019

Answer 42

Cholesterol to pregnenolone (formed in mitochondria)

Question 43

What is the only nuclear receptor and ligand structure that has been structurally solved WIDER READING - Helsen 2012

Answer 43

Retinoid receptor

Question 44

What did this study show regarding the structure of the androgen receptor WIDER READING - Helsen 2012

Answer 44

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.