Lec 11 - Human growth Flashcards
when is max rate of growth
fetus
about 70cm/year
what cell behaviours are affected by growth hormone and IGF-1
- survival (ie prevent or trigger apoptosis)
- hypertrophy
- proliferation
- differentiation
- metabolism
what does hypothal release
ghrh
what type of cell in the APG has the GHRH receptor
somatotrophs
what type of receptor is GHRH receptor
Gs GPCR
activates adenylyl cyclase = cAMP = activation of PKA
what tissues does GH directly act on
- bone
- adipose tissue
- muscle
- liver
where is igf1 produced
in liver mostly (can be in bone)
in response to GH stimulation
where does igf act
- adipose tissue
muscle
etc.
= endorcrine effects - but also bone
= paracrine effects
GH gene
cluster of 5 closely related genes
GH-N = gh normal gene ie the one in circulation
(homology in between species as well)
whivh gh gene expressed in plactena
GH-V
GH-N codes for 2 different variations of GH, what are they
22kDa = the predominant one
20kDa (some residues deleted) = not sure what this one does
Gh produced as a precursor protein, what is cleaved when it gets secreted
n-terminal signal peptide
why would serial sampling be needed to take GH levels
secreted in pulses
and mostly at night
diff between struc of igf1 and gh
igf1 a much smaller peptide than gh
what are the 5 zones in bone
- reserve zone
- proliferative zone
- maturation zone
- hypertrophic zone
- invasion zone
what does reserve zone contain
progenitor cells sat in matrix of collagen
provide cells that feed into next layers
what does proliferative zone contain
chondroblasts organised into columns
what does maturation zone contain
the chondroblasts turn into chondrocytes
these secrete a matrix that forms scaffold for formation of trabecular bone
what does hypertrophic zone
the cells grow in size duh
which then undergo apoptosis
which leave behind lacunae
what does invasion zone contain
osteoblasts come up and deposit bone onto the scaffold left behind by chondrocytes
which zones does gh and igf1 act on
all except invasion zone
what 3 things does GH stimulate in terms of metabolsim
- lipolysis
- amino acid uptake and protein synth
- glucose output from liver
what 3 things does IGF1 stimulate in terms of metbaolism
- lipogenesis
- amino acid uptake and protein synth
- uptake of glucose (similar to insulin)
diff between gh and igf in terms of the receptors
gh receptor has to recruit an enzyme to the recpetor once bound
igf already has catalyitc activity built into the receptor
fast and slow pathways in intracellular signalling
fast = kinase cascades
slow = e.g. GH stimulating production of igf1 by activating the gene
what kind of receptor is GH receptor
homodimer
what is 2 step model of GH biding
- High affinity to first receptor
- Then allows binding to lower affinity site on second receptor
causes conformational change in receptor
= allows recruitment of JAK2 toreceptor
- JAK2 is a kinase = Phosphorylates the receptor
- Allows transc factor called stat5 to bind
- Then stat5 also becomes phosphorylated
- When stat 5 activated = binds to gene with response element (e.g. igf 1 gene)
what is the GHBP
circulating GH is bound to binding protien
The binding protein is the extracellular portion of the protein
A protease cleaves this part off
function of GHBP
Not much known about its significant
Ø May prolong GH half life
May compete GH receptor for GH
what 2 cascades does IGF1 recpeotr trigger when igf binds
- PI-3 kinase pathway
= cell survival, metabolism - MAP kinase
= proliferation
how many igfbps are ther
6
all structually similar
what is the main igfbp
igfbp 3
function of igfbp 3
storage of IGF via ALS
what is ALS
acid labile subunit
a very big complex that binds to IGFBP3
so it cant leave circulation
which keeps igf stored in circ
how does IGFBP stop igf interacting with receptor
have a higher affinity than receptor to igf
what 2 things negative ffedback on system
igf-1 = prevents GH from APG
and
somatostatin = prevents GHRH from hypothal
what is Laron syndrome
mutated GH receptor
what happens if hormone excess
depends if growth plate closed or not
if open = gigantism
if closed = acromegaly (abnormal growth)
treatment of hormone excess
surgery
somatostatin analogue
GH receptor antagonist
