L2 - Cell communication 1 - Hormone signalling pathways

What is the key role of the hypothalamus and pituitary gland?

both play a key role in the maintenance of homeostasis within the body

what is cholesterol?

cholesterol is a lipid with a hydroxyl group on the end (-OH)

what is cholesterol a precursor of?

cholesterol is a precursor of a range of steroid hormones (like cortisol, testosterone, oestradiol, vitamin D3)

what are the properties of steroid hormones?

• hydrophobic properties

• hydrophilic properties

• lipophilic

what do the hydrophilic properties of steroid hormones allow?

allow steroid hormones to dissolve in water and blood

what do hydrophobic properties of steroid hormones allow?

allow steroid hormones to transmit through the lipid bilayer, plasma membrane, and blood brain barrier

what do lipophilic mean?

fat loving

what are the two classes of steroid hormones?

• corticosteroids

• sex steroids

where are corticosteroids made?

adrenal cortex

what are examples of corticosteroids?

• glucocorticoids

• mineralocorticoids

where are sex steroids made?

in the gonads and/or placenta

what are examples of sex steroids?

androgens, oestrogens, progestogens

name the structural components of nuclear receptors:

• N terminal

• DNA binding domain

• Hinge region

• Ligand binding domain

• C terminal

Describe the DNA binding domain:

the domain has a series of conserved cysteine residues which crosslink onto zinc ions to make zinc fingers

what does the DNA binding domain encode?

zinc fingers that contain 4x cysteine residues which co-ordinate with a zinc atom to form a looped structure which them can access the major groove of the DNA double helix

how do zinc fingers give DNA binding specificity?

they are able to give sequence specific DNA binding because the amino acids at the tip of each finger forms non covalent interactions with specific bases in the DNA’s major groove

describe the ligand binding domain

high affinity domain - highly conserved domain throughout various receptors

what does the transcription activating domain on receptors do?

interacts with the transcriptional machinery which switches DNA into RNA and initiates gene expression

explain the steps of ligand binding to a nuclear receptor:

1. The ligand binding domain is empty – inhibitory proteins are bound to keep the receptor inactive

2. The ligand enters the cell and binds to the ligand binding pocket within the ligand binding domain of the receptor

3. The ligand binding domain wraps tightly around the ligand and encloses it

4. The enclosed ligand forms – hydrophobic interactions with the ligand binding domain (LBD) and hydrogen bonds with residues in the LBD à these non-covalent interactions make the binding strong and specific = high affinity

5. the ligand binding causes the receptor to change shape – this change releases the inhibitory proteins and activates the receptor

6. the new receptor shape exposes the AF-2 site on the LBD – co-activator proteins bind and help recruit the transcriptional machinery

7. the receptor then binds to specific DNA sequences and initiates transcription of the target gene causing gene expression

What are the two phases of transcriptional responses to steroid hormone signalling via nuclear receptors?

Primary (early) response and secondary (delayed) response

Primary transcriptional response

• fast (minutes-hours)

• hormone receptor complex binds DNA directly

• activates primary response genes (TFs, regulatory proteins, feedback inhibitors)

• does not require new protein synthesis

Secondary transcriptional response

• delayed (after several hours)

• depends on proteins made during primary response

• activates downstream genes (structural proteins, enzymes)

• requires new protein synthesis

what do proteins made in the primary response activate?

the proteins made in the primary response activate a second set of genes called the secondary response genes

what are glucocorticoids?

a class of steroid hormones - specifically corticosteroids

what are glucocorticoids used for?

• widely used in medical therapy

• they have immunosuppression + potent anti-inflammatory agents

• broad effects on different organ systems

what can a long term use of glucocorticoids lead to?

can lead to serious side effects like bone loss and glucose dysregulation

what is the hypothalamic-pituitary-adrenal (HPA) axis?

the main pathway through which glucocorticoids are produces in the body

describe the HPA (hypothalamic-pituitary-adrenal) axis:

1. The hypothalamus produces CRH (corticotropin releasing hormone)

2. The CHR acts on the pituitary gland

3. The pituitary gland makes ACTH (adrenocorticotropic hormone)

4. The ACTH acts on the adrenal glands on the kidneys

5. The adrenal glands then produce cortisol/dexamethasone (glucocorticoids)

Hypothalamus -> CRH -> pituitary gland -> ACTH -> adrenal glands (kidneys) -> cortisol dexamethasone (glucocorticoids)

what are glucocorticoids released in response to?

stress + reduced blood sugar levels

glucocorticoids are a key part of the bodies response to stress, what else do they affect?

• metabolism

• immune system

• electrolyte balance

• memory

what are the two causes of too little cortisol?

1. primary adrenal insufficiency - damage to adrenal glands

2. secondary adrenal insufficiency - lack of ACTH (adrenocorticotropic hormone) loss of the stimulus that stimulates cortisol

what is the disease associated with too little cortisol?

Addison’s disease

what are the symptoms of Addison's disease?

• depression

• flu-like symptoms

• nausea

• weight loss

what is the Addisonian crisis caused by?

a sudden severe stress

→ accident, operation, infection

what is the disease associated with too much cortisol?

Cushing’s disease

what is the cause of increase levels of cortisol?

• often caused by an adenoma growing in the pituitary gland leading to increased ACTH production (ACTH stimulated adrenal glands = overproducing adrenaline)

• also caused by long term steroid use/abuse

what are the symptoms of Cushing’s disease?

• weight gain

• raised blood pressure

• puffy face

• hair growth

where is insulin made and what is its role?

• made in the pancreas

• plays a crucial role in regulating blood glucose levels (regulated plasma glucose - homeostasis)

what is the process of glucose stimulated insulin secretion?

Increased levels of glucose stimulates beta cells in the pancreas to produce insulin

-> this stimulates the liver, muscles, adipose tissue and other cells in the body to absorb the glucose circulating in the body

-> in the liver – insulin trigger glycolysis, glucogenesis and lipogenesis

-> in other cells – insulin increases glucose transport

-> plasma glucose drops

-> this sends a negative feedback signal to stop further insulin release

-> decreases the activity of beta cells = decreasing the level of insulin = removing the stimulus

what is type 1 diabetes caused by?

• destruction of B cells (beta)

• often as a result of an autoimmune attack

what are the downstream signalling molecules in the insulin signalling pathway?

• IRS1 - Insulin receptor substrate

• Akt - Protein kinase B

  —> both molecules are proteins and key regulators of the insulin signalling pathway

structure of insulin receptor

• made up of two separate protein chains (monomers)

  —> these are made separately, cleaved and then rejoined by di-sulphide bonds (S-S bonds)

  —> pairs of these rejoined receptors then dimerise to form the full receptor - held by more di-sulphide bonds