Endocrine Signalling and the GnRH receptor. Flashcards
What are the different types of receptor in the endocrine system?
GPCR RTKs Ion channels Trans-membrane scaffolds (JAK/STAT?) Guanylyl Cyclase Nuclear Receptors
What are the different types of cell signalling?
Divergent
Convergent
Linear
Multiply branched
Outline the signalling events of G-protein coupled receptors.
Gapla(s) - stimulates adenyly cyclase to produce cAMP from ATP
Ga(i) - opposite effect to the above
Ga(q/11) - leads to phospholipase C activation which converts (PIC) inositol diphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 acts on its receptor to release calcium into the cytoplasm and DAG activates protein kinase C.
The Gbeta-gamma complex can activate ion channels etc. and MAPKs.
What are the types of receptor desensitisation?
Homologous
Heterologous
What are the general families of receptors?
GPCRs JAK/STAT - - RTKs Class I and II nuclear receptors. - I - cytoplasmic, bound to HSPs, homodimerisation - II - nuclear, corepressor binding, heterodimerisation (RXR)
Other than the AP, where can GnRH be transported to?
The limbic system
Where are the different GnRH receptors found?
I - pituitary
II - extrapituitary sites
How does GnRH receptor activation lead to gonadotrophin release?
Activated Ga(q/11) leading to calcium influx which fuses with vesicles containing the hormones.
Ca comes from intra- and extracellular sources (voltage gated ion channels)
Also many other signalling pathways, possibly kinases, cyclic nucleotides, MAPKs.
Ca and DAG can acticavate protein kinases which may lead to increased gene transcription, same with the MAPKs. (This leads to cAMP response binding protein CREB which activates CRE on gonadotroph genes)
What is special about this receptor?
No carboxy tail within the cell so can’t be desensitised quickly.
How is a GPCR normally downregulated?
Phosphorylation of the carboxy terminus allows beta-arrestin binding which would internalise the receptor.
How does this differ for the GnRH receptor?
arrestin must first interact with regulators of g-protein coupled receptors (RGRs)
How are GnRH analogous used?
They eventually lead to down-regulation of the receptor.
How is rapid feedback achieved regarding GnRH pulsality?
GnRH neurons have GnRH receptors
Describe the gonadostat model of puberty onset.
Hypothalamus becomes less responsive to negative feedback from gonadal steroids with age allowing increased GnRH to coincide with puberty.
What studies have put doubt on this hypothesis?
Castrated rhesus monkeys still exhibited pulsality around the time of puberty/suppression of GnRH activity until this time.
Is there another hormone that may be involved in pubertal onset?
Leptin. Although ob/ob mice are still fertile. But also very fat!
