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SoR > Lecture 8: GnRH > Flashcards

Lecture 8: GnRH Flashcards

1
Q

What is GnRH?

A
  • Master controller of reproduction
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2
Q

When was GnRH discovered?

A
  • 1971
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3
Q

Which chromosome contains the gene that codes for GnRH?

A
  • chromosome 8
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4
Q

How many isoforms of GnRH in vertebrates?

A
  • 23
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5
Q

Is GnRH conserved across vertebrates?

A
  • Highly conserved
  • 1 AA substitution max otherwise conserved across species
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6
Q

Which GnRHs are present in vertebrates?

A
  • GnRH I (GnRH) (classical GnRH)
  • GnRH II
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7
Q

What are the roles of GnRH in physiology?

A
  • Neuroendocrine - HPG
  • Paracrine (because GnRHRs present in placenta/gonads)
  • Autocrine (Rs prostate/breast cancer)
  • Neurotransmitter (has affects on other regions of the brain)
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8
Q

What is the structure of GnRH?

A
  • 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)
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9
Q

Where do GnRH neurones originate?

A
  • 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

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10
Q

What is the Placode region?

A

Placode=area of thickening of the embryonic epithelial later from which the organ/structure later develops.

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11
Q

Migration of GnRH neurones

A
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12
Q

What may occur if migration of GnRH neurones goes wrong?

A
  • Results in Hypogonadotrophic Hypogonadism (HH)
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13
Q

Which genes regulate GnRH neurone migration and thus known mutations in them cause HH?

A

-KAL1 (main one),
FGFR1, FGF8, PROK2, PROKR2, NELF, CHD7,
GNRH1, GNRHR, GPR54, TAC3, TAC3R, NKB/NK3R, WDR11

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14
Q

What is a consequence of a mutation in KAL-1 gene?

A

= Kallmann Syndrome
- Premature termination of migration
-> anosmia (inability to smell because GnRH neurones are still in olfactory region) & hypogonadotrophic hypogonadism

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15
Q

Gross anatomy of Parvocellular system

A
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16
Q

How is GnRH released?

A
  • 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
17
Q

How often is GnRH released?

A
  • every 30-120 mins
    via rhythmic pulses “circhoral pulses”
18
Q

How is GnRH released in a pulsatile fashion?

A
  • Via the GnRH Pulse generator
19
Q

What is the GnRH pulse generator?

A
  • collection of hypothalamic neurons producing endogenous secretory rhythms
  • sub-population of kisspeptin neurones in the arcuate nucleus
20
Q

What is the half life of GnRH?

A
  • GnRH t1/2 2-4 minutes

(very short)

21
Q

What does GnRh stimulate?

A
  • synthesis and secretion of gonadotrophins
22
Q

Is the differential frequency and amplitude of GnRH significant?

A
  • Yes
  • alter pattern of FSH and LH secretion, therefore impact gonadal response
23
Q

What is a slow pulse of GnRH responsible for?

A
  • Up-regulation of FSH release
24
Q

What is a fast pulse of GnRH responsible for?

A
  • Up-regulation of LH release
25
Q

Describe the GnRH receptor

A
  • 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
26
Q

What are the two variants of GnRHR?

A
  • Type 1- full length
  • Type 2 - missense truncation ( in humans)
27
Q

What is a missense truncation?

A
  • mRNA for GnRH receptor 2 is expressed and transcribed
  • but actual receptor protein is not available due to missense truncation
28
Q

How is GnRHR resistant to desensitisation?

A
  • C-terminal tail absence
29
Q

What is the significance of the absence of a c-terminal tail?

A
  • 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)
30
Q

Are GnRH neurones only located in the anterior pituitary?

A
  • No!

(cell lines of breast etc shown below containing GnRH neurones)

31
Q

How does GnRH regulate Gonadotrophin production?

A

Rhythm & pulsatility of GnRH
- Relative rates of gene expression for α/β
- Determines dimerisation of subunits
- Determines glycosylation

32
Q

What is the structure of gonadotrophins?

A
  • Glycoproteins with α & β chains
  • α-chains identical in FSH & LH
  • β-chains unique & confer biological actions
33
Q

What does changing GnRH pulse frequency and amplitude cause?

A
  • Switching between FSH and LH synthesis AND secretion.
  • Slow frequency or low amp GnRH pulse ⇒ ⇧FSHb gene expression
  • Fast frequency GnRH pulse ⇒ ⇧LHb transcription
34
Q

Describe GnRH and gonadotrophin patterns in MALESH

A
  • GnRH pulses: constant frequency every 2hr
  • Amplitude varies throughout the day = normal in males
35
Q

Describe GnRH and gonadotrophin patterns in FEMALES

A
  • Higher frequency GnRH pulse (every 30min) = favours LH secretion
  • Lower frequency/amplitude GnRH pulse (every 90-120min) = favours FSH synthesis and secretion
36
Q

How does GnRH differentially regulate FSH and LH production?

A
  • ERK signalling

SoR (12 decks)

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