Lecture 2 - Cell communication I - hormone signalling pathways Flashcards
What is Bisoprolol?
Selective inhibitor of the B1-adrenergic receptor expressed in the heart
How do hormones travel in endocrine signalling?
In the bloodstream
Why do hormone receptors have to be specific?
Hormones travel in low concentrations, so the receptors have to be sensitive enough to detect their presence.
How much oestrogen is found in a lose-dose oral contraceptive?
35ug
What is the roles of the hypothalamus and pituitary gland?
maintenance of homeostasis with the body and act as ‘gateways’ linking the neuronal and endocrinological systems
What makes up approx 30% of all cell membranes?
lipids with an -OH group (about 1g/day) is synthesised in the body
What is cholesterol a precursor of?
Steroid hormones:
- cortisol
- estradoil
- testosterone
- vitamin D3
Describe why it is an advantage that steroid hormones have hydrophilic (-OH group) and hydrophobic (lipid) properties?
They are able to penetrate through cell membranes and the blood/brain barrier.
What 2 classes are steroid hormones grouped into?
- Corticosteroids
- Sex steroids
Where are corticosteroids made?
adrenal cortex
Where are sex steroids made?
gonads and/or placenta
What are the 5 subtypes of steroids - based on what receptors they bind to?
Corticosteroids:
- glucocorticoids
- mineralocorticoids
Sex steroids:
- androgens
- oestrogens
- progestogens
What do the DNA binding domain on receptors encode for?
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.
What are the functional categories of GR (glutocorticoid receptor) targets?
- 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
What occurs in the hypothalamic pituitary adrenal axis?
- 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.
What 2 hormones are released from the hypothalamic pituitary adrenal axis?
Corticotropin-releasing hormone (CRH) - 41aa peptide hormone
Adrenocorticotropic hormone (ACTH) - peptide hormone
What disease results from too little cortisol?
Addisons disease
What disease results from too much cortisol?
Cushings syndrome
What occurs in Addisons disease (too little adrenocorticotropic hormone)?
- 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
What occurs in Cushings syndrome (increase in adrenocorticotropic hormone)?
- 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
What occurs in type 1 diabetes?
destruction of B (beta) cells - often as a result of auto-immune attack.
Prevalence of almost 1:300 by the age of 18.
Describe the formation of insulin
- 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.
What occurs after the conformational change, following the binding of a ligand?
- 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
Describe the 3 biochemical steps in insulin signaling
- Tyrosine phosphorylation of the receptor and its direct substrate (IRS)
- Activation of PI3K, which releases PIP3
- Leads to activation to multiple serine/threonine kinases - most important AKT
What model system is used to study insulin?
Drosophila
What pathway is insulin thought to influence?
lifespan - mutations in AKT (likely to be the basis of ‘calorific restriction’ mechanism of lifespan extension
What is type 2 diabetes mellitus (T2DM)?
- dysregulation of carbohydrate, lipid and protein metabolism
- impaired insulin secretion, insulin resistance or a combination of both.
What are T2DM symptoms?
- feeling thirsty
- passing urine often
- feeling tired
- weight loss
- slow to heal cuts
- frequent vaginal or penile thrush
- blurred vision
Treatment for type 2 diabetes mellitus?
- exercise
- Metformin - antihyperglycemic agent (decrease insulin resistance)
How does Metformin work?
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.
