Lecture 2 - Cell communication I - hormone signalling pathways

Question 1

What is Bisoprolol?

Answer 1

Selective inhibitor of the B1-adrenergic receptor expressed in the heart

Question 2

How do hormones travel in endocrine signalling?

Answer 2

In the bloodstream

Question 3

Why do hormone receptors have to be specific?

Answer 3

Hormones travel in low concentrations, so the receptors have to be sensitive enough to detect their presence.

Question 4

How much oestrogen is found in a lose-dose oral contraceptive?

Answer 4

35ug

Question 5

What is the roles of the hypothalamus and pituitary gland?

Answer 5

maintenance of homeostasis with the body and act as ‘gateways’ linking the neuronal and endocrinological systems

Question 6

What makes up approx 30% of all cell membranes?

Answer 6

lipids with an -OH group (about 1g/day) is synthesised in the body

Question 7

What is cholesterol a precursor of?

Answer 7

Steroid hormones:
- cortisol
- estradoil
- testosterone
- vitamin D3

Question 8

Describe why it is an advantage that steroid hormones have hydrophilic (-OH group) and hydrophobic (lipid) properties?

Answer 8

They are able to penetrate through cell membranes and the blood/brain barrier.

Question 9

What 2 classes are steroid hormones grouped into?

Answer 9

• Corticosteroids
• Sex steroids

Question 10

Where are corticosteroids made?

Answer 10

adrenal cortex

Question 11

Where are sex steroids made?

Answer 11

gonads and/or placenta

Question 12

What are the 5 subtypes of steroids - based on what receptors they bind to?

Answer 12

Corticosteroids:
- glucocorticoids
- mineralocorticoids

Sex steroids:
- androgens
- oestrogens
- progestogens

Question 13

What do the DNA binding domain on receptors encode for?

Answer 13

Zinc fingers, that contain 4x cystine residues, which co-ordinate with a zinc atom to form a looped structure that is able to access the major groove of the DNA double helix.

Question 14

What are the functional categories of GR (glutocorticoid receptor) targets?

Answer 14

• glucocorticoids are used in medical therapy
• immunosuppression and potent anti-inflammatory agents
• broad effects on different organ systems
• long term use can leads to serious side effects - e.g. bone loss and glucose dysregulation

Question 15

What occurs in the hypothalamic pituitary adrenal axis?

Answer 15

• glucocorticoid class steroid hormone is released in response to stress and reduced blood sugar levels. It is a key part of our bodies response to stress. Also effects metabolism, immune system, electrolyte balance and memory.

Question 16

What 2 hormones are released from the hypothalamic pituitary adrenal axis?

Answer 16

Corticotropin-releasing hormone (CRH) - 41aa peptide hormone

Adrenocorticotropic hormone (ACTH) - peptide hormone

Question 17

What disease results from too little cortisol?

Answer 17

Addisons disease

Question 18

What disease results from too much cortisol?

Answer 18

Cushings syndrome

Question 19

What occurs in Addisons disease (too little adrenocorticotropic hormone)?

Answer 19

• Primary adrenal insufficiency: damage to the adrenal glands
• Secondary adrenal insufficiency: (lack of ACTH)
• Depression, flu-like symptoms, nausea, weight-loss
• Addisonian crisis - caused by sudden severe stress e.g. accident, operation, infection

Question 20

What occurs in Cushings syndrome (increase in adrenocorticotropic hormone)?

Answer 20

• Increased levels of cortisol
• E.g. an adenoma growing in the pituitary gland leading to increased ACTH production
• Caused by long-term steroid use/abuse
• Weight gain, raised blood pressure, puffy fair, hair growth

Question 21

What occurs in type 1 diabetes?

Answer 21

destruction of B (beta) cells - often as a result of auto-immune attack.
Prevalence of almost 1:300 by the age of 18.

Question 22

Describe the formation of insulin

Answer 22

• each half is transcribed as monomer, cleaved, rejoined by di-sulphide bonds. Pairs of rejoined receptors dimerise and are linked by more di-sulphide bonds. Tyrosine kinase activity follows, with ligand binding triggering a conformational change.

Question 23

What occurs after the conformational change, following the binding of a ligand?

Answer 23

• moves 2 kinase domains closer together
• kinase domains trans-phosphorylate
• in addition, a closely associated docking protein INSULIN RECEPTOR SUBSTRATE 1 (IRS1) also becomes tyrosine phosphorylated

Question 24

Describe the 3 biochemical steps in insulin signaling

Answer 24

1. Tyrosine phosphorylation of the receptor and its direct substrate (IRS)
2. Activation of PI3K, which releases PIP3
3. Leads to activation to multiple serine/threonine kinases - most important AKT

Question 25

What model system is used to study insulin?

Answer 25

Drosophila

Question 26

What pathway is insulin thought to influence?

Answer 26

lifespan - mutations in AKT (likely to be the basis of ‘calorific restriction’ mechanism of lifespan extension

Question 27

What is type 2 diabetes mellitus (T2DM)?

Answer 27

• dysregulation of carbohydrate, lipid and protein metabolism
• impaired insulin secretion, insulin resistance or a combination of both.

Question 28

What are T2DM symptoms?

Answer 28

• feeling thirsty
• passing urine often
• feeling tired
• weight loss
• slow to heal cuts
• frequent vaginal or penile thrush
• blurred vision

Question 29

Treatment for type 2 diabetes mellitus?

Answer 29

• exercise
• Metformin - antihyperglycemic agent (decrease insulin resistance)

Question 30

How does Metformin work?

Answer 30

Inhibits mitochondrial complex I, preventing production of mitochondrial ATP, leading to increased cytoplasmic ATP.
Changes activate AMPK (AMP kinase), an enzyme that plays an important role in regulation of glucose metabolism.