Lecture 8: GnRH Flashcards
What is GnRH?
- Master controller of reproduction
When was GnRH discovered?
- 1971
Which chromosome contains the gene that codes for GnRH?
- chromosome 8
How many isoforms of GnRH in vertebrates?
- 23
Is GnRH conserved across vertebrates?
- Highly conserved
- 1 AA substitution max otherwise conserved across species
Which GnRHs are present in vertebrates?
- GnRH I (GnRH) (classical GnRH)
- GnRH II
What are the roles of GnRH in physiology?
- Neuroendocrine - HPG
- Paracrine (because GnRHRs present in placenta/gonads)
- Autocrine (Rs prostate/breast cancer)
- Neurotransmitter (has affects on other regions of the brain)
What is the structure of GnRH?
- Peptide
- Pre-pro hormone
-> Proteolytic cleavage => Mature GnRH & GnRH associated protein (GAP) - GnRH is a decapapetide (10 AA long)
- GAP peptide- co-secreted with GnRH - unknown function (no ongoing research on GAP)
Where do GnRH neurones originate?
- They do not originate in Hypothalamus -> have to migrate there:
Embryonic period:
- Originate outside CNS, in medial olfactory placode
- Cells migrate:
- Nasal region -> brain -> medio-basal hypothalamus
- Numerous genes involved
What is the Placode region?
Placode=area of thickening of the embryonic epithelial later from which the organ/structure later develops.
Migration of GnRH neurones
What may occur if migration of GnRH neurones goes wrong?
- Results in Hypogonadotrophic Hypogonadism (HH)
Which genes regulate GnRH neurone migration and thus known mutations in them cause HH?
-KAL1 (main one),
FGFR1, FGF8, PROK2, PROKR2, NELF, CHD7,
GNRH1, GNRHR, GPR54, TAC3, TAC3R, NKB/NK3R, WDR11
What is a consequence of a mutation in KAL-1 gene?
= Kallmann Syndrome
- Premature termination of migration
-> anosmia (inability to smell because GnRH neurones are still in olfactory region) & hypogonadotrophic hypogonadism
Gross anatomy of Parvocellular system
How is GnRH released?
- GnRH is processed & packaged into storage granules
- transported down the axons to external zone of median eminence
- GnRH released in synchronized pulses from GnRH nerve endings into hypophyseal portal system
How often is GnRH released?
- every 30-120 mins
via rhythmic pulses “circhoral pulses”
How is GnRH released in a pulsatile fashion?
- Via the GnRH Pulse generator
What is the GnRH pulse generator?
- collection of hypothalamic neurons producing endogenous secretory rhythms
- sub-population of kisspeptin neurones in the arcuate nucleus
What is the half life of GnRH?
- GnRH t1/2 2-4 minutes
(very short)
What does GnRh stimulate?
- synthesis and secretion of gonadotrophins
Is the differential frequency and amplitude of GnRH significant?
- Yes
- alter pattern of FSH and LH secretion, therefore impact gonadal response
What is a slow pulse of GnRH responsible for?
- Up-regulation of FSH release
What is a fast pulse of GnRH responsible for?
- Up-regulation of LH release
Describe the GnRH receptor
- G-protein-coupled receptor (GPCR)
- Two variants: Type I and II GnRHR
- Resistant to desensitisation (some exceptions)
- Mainly expressed on gonadotroph cells of anterior pituitary
What are the two variants of GnRHR?
- Type 1- full length
- Type 2 - missense truncation ( in humans)
What is a missense truncation?
- mRNA for GnRH receptor 2 is expressed and transcribed
- but actual receptor protein is not available due to missense truncation
How is GnRHR resistant to desensitisation?
- C-terminal tail absence
What is the significance of the absence of a c-terminal tail?
- Evolutionary benefit
- Absence = renders GnRHR resistant to desensitation (via C-terminal) (in the classical sense)
- overexposure to ligand - receptor is desnesitised. This process occurs by C-terminal tail being phosphorylated and receptor is then internalised into the cell (classical desensitisation of a receptor in cell biology)
Are GnRH neurones only located in the anterior pituitary?
- No!
(cell lines of breast etc shown below containing GnRH neurones)
How does GnRH regulate Gonadotrophin production?
Rhythm & pulsatility of GnRH
- Relative rates of gene expression for α/β
- Determines dimerisation of subunits
- Determines glycosylation
What is the structure of gonadotrophins?
- Glycoproteins with α & β chains
- α-chains identical in FSH & LH
- β-chains unique & confer biological actions
What does changing GnRH pulse frequency and amplitude cause?
- Switching between FSH and LH synthesis AND secretion.
- Slow frequency or low amp GnRH pulse ⇒ ⇧FSHb gene expression
- Fast frequency GnRH pulse ⇒ ⇧LHb transcription
Describe GnRH and gonadotrophin patterns in MALESH
- GnRH pulses: constant frequency every 2hr
- Amplitude varies throughout the day = normal in males
Describe GnRH and gonadotrophin patterns in FEMALES
- Higher frequency GnRH pulse (every 30min) = favours LH secretion
- Lower frequency/amplitude GnRH pulse (every 90-120min) = favours FSH synthesis and secretion
How does GnRH differentially regulate FSH and LH production?
- ERK signalling
