Nuclear Receptors

Question 1

Define steroid hormones + their importance (2)

Answer 1

Small lipophilic molecules that can diffuse through cell membranes, RAPIDLY -> important because they can be produced in the periphery but can easily get into the brain

Question 2

Give examples of the main steroid hormones (6)

Answer 2

• Testosterone
• Estradiol
• Progesterone
• Glucocorticoids (“glucose + cortex + steroid”) I.e. cortisol (humans) or corticosterone (rodents)
• Mineralocorticoids - I.e. aldosterone (salt/H2O)
• Thyroid hormones

Question 3

Walk through the steroid hormone receptor mechanism (8)

Answer 3

1) Hormone (H) circulates + binds to binding globulin

2) H released from binding globulin

3) H freely diffuses across membrane because they are lipid soluble

4) Unoccupied steroid H receptors (SHR) are bound to HSP90

5) H binding to receptor dissociates HSP90 (releases HSP90)

6) Hormone receptor complex forms and then SHR complex dimerises

7) SHR dimer enters nucleus -> translocates + binds to RNA polymerase + TF’s

8) Regulates gene expression

Question 4

What ways can steroid hormone receptors impact transcription? (5)

Answer 4

+GRE = Positive GRE (bind GR dimers) - activation

nGRE = Negative GRE (bind GR dimers) - repression

cGRE = Composite GRE (GR + txn factors) – activation or repression -> KNOWN AS TETHERING

tGRE = Tethering GRE (GR + txn factors with txn factors NOT GR bound to DNA) activation or repression

Steric hinderance – GR bound to DNA can prevent txn factor binding or prevent txn machinery binding. - repression

Question 5

What are the common structural elements? (4)

Answer 5

NTD – important for activation of gene expression

DNA-binding domain (DBD) – binds to the hormone response element (HRE) in genes

Hinge domain – together with the DBD are important for nuclear localisation

Hormone binding domain – these are unique for each hormone

Question 6

approx. how many members are in the steroid receptor ‘superfamily’ (2)

Answer 6

They are approx 40 members, with a range of responsibilities e.g. reproduction, whole body metabolism –> glucose homeostasis

Question 7

Non-genomic mechanisms of steroid signalling (4 + 2)

Answer 7

-Membrane steroid hormone receptors coupling through GPCR modulating ion channel activity

-Membrane steroid hormone receptors coupling through GPCR modulating intracellular signaling cascades

-Steroid hormone metabolites modulating neurotransmitter receptor activity

-Steroid hormones binding phospholipids to impact membrane flexibility and thus function of ATPases

they alter neurotransmitter receptors levels –> neurotransmitter/neurosteroid synthesis or storage

Question 8

What are the non- genomic actions of the steroid hormones? (3)

Answer 8

-Pre-optic area of the hypothalamus

-Both excitation and inhibition

-Rapid onset and rapid termination