role of hypothalamus
- regulates response to external environment (senses)
- regulates response to internal environment (extra/intracellular levels)
- regulates behaviour (reproductive, feeding, rage)
- maintains homeostasis (body temp, metabolism, etc)
cells/hormones in the anterior pituitary gland
- thyrotrophs –> thyroid stimulating hormone (TSH) –> thyroid gland
- corticotrophs –> ACTH –> adrenal cortex
- somatotrophs –> growth hormone (GH) –> liver and other tissues
- gonadotrophs –> LH and FSH –> gonads
- lactotrophs –> prolactin (breast)
capillaries and where they’re found:
- continuous
- fenestrated
- sinusoidal (discontinuous)
- continuous
- endothelial cells compact to form one cell to encompass capillary wall
- very common - fenestrated
- larger gaps between cells
- more leaky than continuous
- allows easy passage in/out of circulation
- found in anterior pituitary - sinusoidal (discontinuous):
- very large gaps between cells
- found in liver
hormone release from anterior pituitary
RF and RIFs of ant/ pituitary hormones
- releasing factors (neurohormones) released at median eminence (base of hypothalamus) into portal veins
- travel down capillary stalk to anterior pituitary
- act on target cells to stimulate synthesis and secretion of hormones
- RFs rapidly metabolised
- TSH
RF = TRH
RIF = none - ACTH
RF = CRH
RIF = ? - GH
RF = GHRH
RIF = somatostatin - LH + FSH
RF = GnRH
RIF = GnIH - prolactin:
RF = ?
RIF = dopamine
GH signalling
GH signals through JAK/STAT pathway. GH receptors found in most tissues
- receptor activated when GH binds to two receptor arms
- JAK2 activated then phosphorylated
- JAK2 then phosphorylates part of receptor
- conformational change –> STAT molecules bind
- STAT molecules phosphorylated –> move to nucleus
spontaneous prolactin secretion from lactotrophs
occurs in absence of dopamine
- change in MP
- VG Ca2+ channels open –> calcium influx
- increase in intracellular calcium causes vesicle secretion = endocytosis of prolactin
upstream, cAMP very important in pathway
1) activation of AC
2) convert ATP to cAMP
3) cAMP cellular messenger –> membrane depolarisation
how does dopamine act to prevent prolactin secretion from lactotrophs?
dopamine D2 receptor (GPCR) turns off AC therefore inhibits cAMP production
results in hyperpolarisation of cell, less spontaneous depolarisation and calcium influx = less prolactin release
inhibits:
1) cyclin cAMP
2) inhibits depolarisation
3) inhibits calcium influx
milk ejection from breat
prolactin targets alveolar epithelial cells in breast
prolactin pushes milk into lumen of epithelial cells
alveolar epithelial cells are surrounded by myoepithelial cells
oxytocin causes contraction of these myoepithelial cells to eject milk from lumen
PRL receptor signalling (non-lactating)
prolactin binds to dimer of receptor (binds to both arms)
activates JAK2 enzyme by phosphorylation
activates intracellular domains of receptor i.e. tyrosine residues
STAT 5 molecules dock as phosphorylated sites
JAK 2 then phosphorylates STAT 5
STAT 5 forms dimers and enters nucleus
STAT acts as TF: bind to promoter region on genes to activate transcription
regulation of prolactin levels
regulated by short loop negative feedback
dopamine constantly released to maintain low levels of prolactin in non-lactating individual:
- inhibits both synthesis and secretion
tyrosine hydroxylase is a rate-limiting enzyme which produces dopamine
high prolactin = JAK/STAT pathway = switch on tyrosine hydroxylase = increased dopamine = supress prolactin
in a lactating individual, the negative feedback loop is disrupted
sucking stimulus = neural feedback to hypothalamus = less dopamine released = more prolactin = milk production/release
PRL receptor signalling (lactating)
prolactin binds to receptor as normal but JAK/STAT pathway does not occur
no up-regulation of tyrosine = hydroxylase = no additional dopamine
SOCS = suppressors of cytokine signalling
CIS = prevents STAT binding
SOCS 1 = prevents JAK phosphorylation
SOCS 3 = “ “ also prevents STAT docking
SOCS 2 = targets whole receptor for degradation
hormones in posterior pituitary gland
2 main hormones:
- vasopressin / anti-diuretic hormone (ADH)
- oxytocin
both peptides with 9 aa residues
hormones expressed in paraventricular nucleus (PVN) supraoptic nucleus (SON)
travel down axons to reach posterior pituitary
vasopressin / ADH action and regulation (general)
actions:
- decreases water excretion in kidneys
- vasoconstriction –> increase blood pressure
regulated by:
- concentration in ECF
- blood volume i.e. stretch receptors in heart send neural feedback to hypothalamus to control ADH neurones (switch off = more urine loss)
oxytocin action and regulation
actions:
- parturition: stimulates contraction of uterine smooth muscle
- lactation: milk ejection during breastfeeding due to contraction of smooth muscle
regulated by:
1) pressure of baby in birth canal
2) sucking baby
- increases mRNA production in SON and PVN
3) oestrogen up-regulates mRNA transcription of oxytocin (and prolactin)
4) fear/anxiety suppresses oxytocin
oxytocin cell signalling pathway
oxytocin binds to oxytocin receptor (GPRC - Gq)
Gq activates phospholipase C (PLC)
PLC produces IP3
IP3 moves through cytoplasm and binds to receptors on SR/ER
causes calcium release from SR/ER
calcium facilitates actin myosin cross bridge formation
results in muscle contraction and milk ejection
