lecture - neurohypophysis, AVP, and oxytocin

what are magnocellular neurons

neurons in hypothalamus that have larger axons that extend to neurohypophysis aka post pit

located in PVN and SON

how do neuropeptides produced in magno neurons reach their release site

neuropeptides go down the magno neuron axons into post pit where they are directly released into general circulation

what is the release site of neuropeptides from magno neurons

released from post pit directly into general circulation

released in larger quantities as they do go directly into circulation

what are the 2 main neuropeptides released by magno neurons

vasopressin - AVP/ADH

oxytocin

the PVN has what kind of neurons

magno and parvo neurons

the SON has what kind of neurons

only magno neurons

does SON or PVN produce most of the AVP

SON produces 80-90% of AVP

what are neurophysins and what role do they play in production of AVP and OT

part of precursor molcs of AVP and OT that are critical for proper protein folding

where are neurophysins removed from hormone molc

they are packed in secretory granules alongside the hormone and cleaved during axonal travel

do neurophysins get released along with OT and if it does what role does it play post secretion

NP I does get released with OT but not sure of role

NP I is part of

OT prehormone

NP II is part of

AVP prehormone

what role does electrical activity of magno neurons play with release of nonapeptides

helps to speed rate of axonal flow by depolarizing the mem to allow Ca to rush in

what role does Ca play in the release of nonapeptides

upon entry, Ca triggers exocytosis of hormone vesicles into extracellular space in synaptic cleft which are they are then absorbed into the blood

what are the 2 main types of AVP receptors

V1R and V2R

what are the 2 main effects of AVP

regulation of water

vasoconstriction/dilation

describe V2R

found in kidney principle cells of collecting tube

stimulated by osmoreceptors

regulates regulation of water

describe V1R

found in blood vessels

stimulated by baroreceptors

regulates vasoconstriction/dilation

what are osmoreceptors

receptors that respond to changes in blood osmolarity

respond to things like dehydration and or more salt in stuff in blood

where are osmoreceptors related

IN the hypothalamus

high osmolarity triggers...

release of AVP from post pit

what major physiological effect does AVP binding to V2R have

causes renal water absorption which leads to inhibition of further AVP release via osmoreceptors

what kind of receptor is V2R

GPCR that uses Gs → cAMP/PKA pathway

what are the short term effects of AVP binding to V2R

causes aquaporin 2 (Aqp2) translocation to apical cell mem to get more water intake

what are the long term effects of AVP binding to V2R

increases expression of Aqp2 and Aqp3 in principle cells of kidney

what are aquaporins

pores for which water can pass through

describe Aqp1

always open in descending loop of Henle/proximal tube

describe Aqp2

in apical mem of principle cells of collecting duct of kidney

ONLY Aqp that is responsive to AVP binding

describe Aqp3/4

in basolateral mem of principle cells of collecting duct of kidney

what are principle cells

cells that line the collecting duct of kidney, allows for H2O absorption in collecting duct

only part of kidney where AVP can bind and function

what kind of receptor is V1R

GPCR that uses Gq → Ca signaling with PIP2/IP3

activation of V1R causes

vasoconstriction

what are baroreceptors

receptors that respond to changes in blood volume/pressure

Where are baroreceptors located

in blood vessels

sends signals TO hypothalamus

what can trigger baroreceptors

things like a drop in blood pressure from hypovolemia or hypotension causes signal to be sent to magno neurons to release AVP from post pit

describe what happens to blood osmolarity with dehydration

blood osmolarity ↑ → AVP release from post pit → binds to V2R in collecting duct of kidneys → ↑ water absorption via Aqp2 → blood osmolarity ↓ → inhibition of AVP via osmoreceptors

describe what happens to blood pressure with dehydration

blood pressure ↓ → baroreceptors send signal to hypothalamus → AVP release from post pit → binds to V1R causing vasoconstriction → blood pressure ↑ → AVP inhibition feedback

diabetes insipidus is a consequence of

AVP deficiency

what are the 2 types of diabetes insipidus

neurogenic and nephrogenic

describe neurogenic diabetes insipidus

caused by mutations that inactivate AVP

source not working

describe nephrogenic diabetes insipidus

caused by mutations in V2R or Aqp2

target not working

which version of diabetes insipidus is easier to treat

neurongenic imo as rest of the pathway is intact so injections could solve the problem

what can be a model for neurogenic diabetes insipidus

brattleboro rats

what is oxytocin and where is it produced

nonapeptide made by magno neurons

secreted by post pit into general circulation

what general effect does oxytocin have on target tissues

involved in contractions of smooth muscles, parental bonding, maternal behavior, and in milk letdown

what kind of receptor is OTr

GPCR that uses Gq → Ca signaling with PIP2/IP3

what specific cell layer of the uterus is the primary target of OT

myometrium

what effect does priming with estrogen (E) and progesterone (P4) have on myometrium

E stimulates synth of OT + OTr

E + P4 cause coordinated and strong myometrial contraction

describe the ferguson reflex

cervical/vaginal dilation stimulates release of more OT

positive feedback loop

what are the steps of the ferguson reflex

fetal pressure on birth canal → magno release of OT → contraction of myometrium → fetal expulsion

in what part of the uterus is OTr more abundant

fundus of uterus

what does OT promote

synth of prostaglandins to facilitate cervical opening

promotes gap junction expression in uterus to make contractions more effective

what is milk letdown

release of milk

how does OT affect milk letdown

triggers contractions of alveoli to pump milk

what are the steps of milk letdown

suckling → mechanoreceptors in breast → signal to brain → magno release of OT → pumping of alveoli → milk letdown

what specific cells in the mammary are the targets of OT

myoepithelial cells

what stimulus leads to OT release and subsequent milk letdown

sucking stimulus

describe the process of AVP/OT release from creation to secretion

mRNA exported from nucleus → precursor protein synth in RER → packaged in secretory granules as precursor protein with cleavage enzymes → cleavage occurs as granules travel through axon body → release in equal concentrations with corresponding NP in response to stimulus

what larger, the AVP/OT prohormone or the hormone

prohormones

what are the secondary effects of AVP

stimulation of ACTH secretion via V3R

stimulation of factor VIII in blood clotting via V2R

what is hypovolemia

low blood volume

what is hypotension

low blood pressure

is AVP's role in hydric balance or as a pressor function more important

role in hydric balance is more important

why are brattleboro mice good models for neurogenic diabetes insipidus

strain of rat with genetic mutation making them unable to make AVP

mutation is on NP II

what diabetes symptoms do brattleboro mice always show

polyuria, polydipsia

what are some ways to cause neurogenic diabetes insipidus

no AVP production or release

severing of nerve axons

what are some ways to cause nephrogenic diabetes insipidus

mutations in V2R or AQP2

absence of OT during milk letdown results in what for the baby

neonatal death by dehydration via lack of milk