Nandralone - steroid hormones Flashcards
what are steroid hormones derived from
cholesterol
where are steroid hormones typically made
in the periphery
endocrine glands
e.g. adrenal cortex and gonads
when are steroid hormones biologically active
when they are circulating in their ‘free’ state
what allows steroid hormones to pass through the BBB
they are lipid/fat soluble
pass through via transmembrane diffusion
how are steroid hormones carried in the blood
bound to proteins (globulins) or albumin (plasma protein)
testosterone conversion in the brain
converted to oestradiol by aromatase enzyme and then to oestrogen
neuroactive steroid
steroid that can act within the brain
neurosteroid synthesis
steroid made within the brain
directly synthesised from cholesterol in the brain
examples of neurosteroids
Pheromones
progesterone
Allopgrenanolone
Dehydroepiandrosterone (DHEA)
examples of neuroactive steroids
Oestradiol Progesterone Testosterone Glucocorticoid Dehydroepiandrosterone (DHEA)
Hypothalamic–pituitary–gonadal (HPG) axis importance
how the brain controls production of steroids within in the gonads
features of how neuroactive steroids modulate activity of cells
regulatory function
slow - over hours, number of days
genomic action, passes through lipid membrane, enters nucleus and alters gene transcriptions to elicit downstream effects
non genomic action of steroids
can be neurosteroids or neuroactive steroids
fast
seconds to minutes
neuromodulatory function
activation of a second messenger molecule
steroid receptors of the nuclear receptor family are all…
transcription factors
how many different domains on a nuclear steroid hormone receptor
5
which domain is the most variable
the N-terminal
AF1 co-activator region
importance of the variable N-terminal domain
binds transcription factors
determines receptor activity
different in length between different receptors
why is the core DNA binding domain important
regulates receptor dimerisation
controls which genes will be activated
where does the core DNA binding domain bind to in DNA
hormone response elements (HRE)
which domain of the steroid hormone receptor is highly conserved
core DNA binding domain
importance of the hinge region domain
Flexible
Regulates dimerization
DNA binding
controls the movement of the receptor to the nucleus.
role of AF2 co-activator region domain
ligand binding domain
where hormones bind
induce nuclear localisation signal (NLS)
role of c-terminal domain
extension that connects the molecule to its pair in the homodimer or heterodimer.
may affect the magnitude of the response.
hsp binding
receptor may bind to chaperone proteins
AF1 stands for
activator function 1
LBD stands for
ligand-binding domain
DBD stands for
DNA binding domain
ER subtypes
estrogen receptor subtypes alpha and beta
PR subtypes
progesterone receptor subtypes A and B
what are MR and GR
mineralocorticoid receptor
glucocorticoid receptor
what enables a single steroid hormone to have many different behavioural effects within the brain
interconversion by metabolites eg. aromatase
2 types of steroid hormone receptors
membrane steroid hormone receptors
nuclear steroid hormone receptors
non-genomic action of steroids to control cell activity
neuromodulatory - FAST
bind to membrane steroid hormone receptor
activate 2nd messenger signalling cascade
genomic action of steroids
regulatory - SLOW bind to nuclear steroid hormone receptor translocates to nucleus activate transcription factors transcribed genes mediate downstream effects
more often neuroactive steroids e.g. oestrogen/testosterone
highly specific region of nuclear steroid hormone receptor
ligand binding domain
GRE
glucocorticoid response element
genes that can be influenced by the presence of glucocorticoid steroid hormone
positive glucocorticoid RE
when GR dimers bind and results in activation of transcription
-ve GRE
involved in repression
when glucocorticoid receptors bind to transcription factors and stop genes being transcribed
steric hindrance of GRE
when GR is bound to DNA
doesnt stop transcription directly
stops transcription factor binding close by
indirectly prevents transcription machinery transcribing a gene close to a GRE
tethering GRE
when GR bind T factors but dont bind the DNA
how can steroid hormones act via non-genomic mechanisms to alter ATPase activity
bind to phospholipids in membrane bilayer
impact membrane flexibility
effect of allopregnanolone on GABA A receptors
positive allosteric modulator
why is chronic stress dangerous
glucocorticoid receptors all over the body
GRE present in 20% of all genes in the genome
CRH neurons
corticotropin releasing hormone
where are CRH found
paraventricular nucleus of the hypothalamus
project to pituitary gland
effect of chronic early life stress on GR expression
reduces GR expression (down-regulation) in the CNS
reduced negative feedback inhibition of the HPA axis
alters ability to cope with stress in later life
which is faster genomic or non-genomic
non-genomic
