L2: cell communication 2 (hormone pathways)

state an adaptation of hormone receptors

specific and sensitive enough to detect low concentrations of hormones

what is the typical dosage of a low-dose oral contraceptive pill

35μg oestrogen

which structures in the brain maintain homeostasis

hypothalamus and pituitary gland

what is the importance of cholesterol

lipid with an -OH group (alcohol) making up ~30% of all cell membranes 

~1g/day is synthesised via a 37 step biosynthetic pathway

precursor to range of steroid hormones

describe the properties of steroid hormones

have both hydrophilic -OH group and hydrophobic lipid properties so are able to penetrate through cell membranes + blood/brain barrier, and aqueous environments

name the 2 main classes of steroid hormones and what differentiates them

corticosteroids made typically in the adrenal cortex

sex steroids made typically in the gonads/placenta

name the 5 sub-types of steroid hormones and which receptors they bind

glucocorticoids (corticosteroid)

mineralocorticoids (corticosteroid)

androgens (sex steroid)

oestrogens (sex steroid)

progestogens (sex steroid)

how is zinc involved in gene regulation

the DNA binding domain encodes ‘zinc fingers’ containing 4 cystine residues coordinating with a zinc atom to form a looped structure able to access the major groove of DNA double helix

how are all nuclear receptors similar

all share a similar primary structure + a similar tertiary structure

describe the primary (early) response of a nuclear receptor to a steroid hormone

receptor-steroid-hormone complexes activate primary response genes → induce synthesis of primary response proteins

describe the secondary (delayed) response of a nuclear receptor to a steroid hormone

a primary response protein shuts off primary response genes + turns on secondary response genes

how are glucocorticoids used clinically

widely used as immunosuppression and potent anti-inflammatory agents with broad effects on different organ systems

long term use can leads to serious side effects (bone loss, glucose dysregulation)

dexamethasone used clinically which is very similar but more potent

what specific effects does cortisol have

affects metabolism, immune system, electrolyte balance, memory

describe the typical cortisol release pathway

corticotropin releasing hormone (CRH - 41aa peptide hormone) released from the hypothalumus stimulated the pituitary gland to release adrenocorticotropic hormone (ACTH - peptide hormone) which stimulates synthesis of cortisol from the adrenal glands in response to stress + reduced blood sugar levels.

name the disease that occurs when there is too little cortisol

addison’s disease

describe the disease which occurs when there is too little cortisol

damage to adrenal glands causes primary adrenal insufficiency (not enough CRH) → secondary adrenal insufficiency (not enough ACTH)

what are the symptoms of too little cortisol

depression, flu-like symptoms, nausea, weight loss, Addisonian crisis (caused by sudden stress)

what disease is caused by too much cortisol

cushing’s syndrome

describe the disease which occurs when there is too much cortisol

tumour in pituitary gland or adrenal glands cause too much cortisol to be released, also caused by long term steroid abuse

what are the symptoms of too much cortisol

weight gain, raised blood pressure, puffy face, hair growth

what causes type 1 diabetes

destruction of β cells often as a result of an auto-immune attack

describe the structure of an insulin receptor

2 alpha subunits in the EC space, bind insulin

2 transmembrane beta subunits containing the tyrosine kinase domains which autophosphorylation when activated

subunits connected via disulphide bonds

how are insulin receptors formed

each half transcribed as a monomer, cleaved, and rejoined bydisulphide bonds

pairs of rejoined receptors dimerise and are linked by more disulphide bonds

ligand binding triggers conformational change

what happens when insulin binds to an insulin receptor

conformational change triggered which moves 2 kinase domains closer together which transphosphorylase

a closely associated docking protein IRS1 (insulin receptor substrate 1) also becomes tyrosine phosphorylated 

what are the 3 major biochemical steps in insulin signalling 

tyrosine phosphorylation of insulin receptor + its direct substrates (IRS)

activation of PI3K lipid kinase

activation of multiple serine/threonine kinases - most importantly AKT

explain in detail the insulin biochemical signalling pathway

tyrosine phosphorylation of insulin receptor + its direct substrates (IRS)

p-Tyrosine sites on IRS allow binding of lipid kinase PI3K which synthesises PIP3 at the plasma membrane

PIP3 recruits PDK (phosphoinositide-dependent kinase) which directly phosphorylates the Thr308n residue of AKT

activated AKT goes onto phosphorylate a number of substrates at Ser/Thr residues

which Ser/Thr residues are phosphorylated by AKT

FOXO transcription factors (forkhead family box O)

TSC2 protein (tuberous sclerosis 2) which permits activation of mTORC1 + downstream targets of S6K (ribosomal protein S6 kinase) + SREBP1 (sterol regulatory element binding protein 1c)

GSK3β (glycogen synthase kinase 3β

TBC1D4 (RabGAP TBC1 domain family member 4)

name the 2 types of insulin used to treat type 1 diabetes and when are they used

long acting ‘background’ insulin replacement

fast acting ‘bolus’ with meals 

what is caused by excess insulin

hypoglycaemia

what are the symptoms of hypoglycaemia

hungriness, sweating, sleepiness, shakiness, headache, confusion, ultimately unconsciousness + death

what is caused by excess glucose in the blood

hyperglycaemia

what are the symptoms of hyperglycaemia

increased thirst, fatigue, excess urination, retinal damage/blindness, foot ulcers, various other serious complications

what causes type 2 diabetes mellitus

dysregulation of carbohydrate, lipid, and protein metabolism 

impaired insulin secretion, insulin resistance, or a combination of both

describe the typical symptoms of type 2 diabetes mellitus

feeling very thirsty

passing urine more frequently than usual - particularly at nigh

fatigue

weight loss/loss of muscle bulk

slow to heal cuts/ulcers

frequent vaginal or penile thrush

blurred vision

what is the treatment for T2DM

weight loss - can be helped using GLP-1 agonists (e.g. semaglutide/ozempic)

how does semaglutide/ozempic treat T2DM

increases GLP-1R stimulation → increase ‘fullness’ hormone levels 

signals via AKT (S/T kinase central to insulin pathway)