L9 - neuropeptide traansmitters Flashcards
what are the families of neuropeptides
- neurokinins (including substance P) -> sensory transmitters
- enkephalins and opioid peptides
- Neuropeptide Y (NPY) and analogues
- vasoactive intestinal Polypeptide (VIP)
- CGRP (calcitonin gene related peptide)
many more
describe neuropeptide synthesis
they are cleaved from larger inactive precursors by enzymes then transported to golgi for packaging into large dense- core vesicles
how was substance P discovered
von euler and goddum were studying ACh when they discovered a substance that was insensitive to atropine but could cause elevated blood pressure and gut smooth muscle contraction
what effect do enkephalins have?
analgesia
are expression levels of neuropeptides constant
no they can vary depending on pathology, or nerve injury
describe the processing of NPY
gene transcribed into precursor which is cleaved giving NPY and CPON (C-terminal peptide of NPY) which is inactive
precursor must have an NH2 group added post-transcriptionally to its C terminal for NP to be active
what two genes are responsible for production of Substance P and NKs
PPT1
PPT2
preprotachykinin 1&2
what are the main neuropeptides produced by PPT1
substance P and NKA
often co expressed
(predominantly found in enteric nervous system)
what are the main neuropeptides produced by PPT2
NKB
where is substance P found
CNS
ENS
sensory nerves
describe the degradation of neuropeptides
non specific unlike other NTs
one enzyme can degrade many neuropeptides
give example of enzyme that degrades neuropeptides and give examples of what it can degrade
enkephalinase
can degrade:
- Met and Leu enkephalins
- SP
- NKA
- NKB
- NPY
describe the mechanism of neuropeptide degradation by enkephalinase (NEP)
NEP -> natural endopeptidase
- enkephalinase cleaves the protein between a Hphobic residue and a tyrosine/phenylalanine
if the peptide doesnt have this in its sequence it wont be degraded by enkephalinase
what effect does phosphoramidon have
phosphoramidon is a high affinity NEP inhibitor and so will prolong and exaggerate effects of Neuropeptides
name a NEP inhibitor
phosphoramidon
what else, other than NEP can degrade NPY
aminopeptidase DPPIV
describe mechanism of degradation of NPY by aminopeptidase DPPIV
- aminopeptidase cleaves 2 AAs from the N terminal of NPY
2. this cleavage forms NPY 3-36
what effect does amiopeptidase degradation have on NPY receptor activation
NPY can activate receptors Y1 and Y2
after degradation to NPY(3-36), this peptide can activate Y2 receptors but not Y1
so aminopeptidase degradation doesnt fully inactivate NPY but changes its singalling ability
are neuropeptides re-uptaken
no, just degraded
what receptors are activated by NPY 3-36
Y2 only
what type of vesicles are normal NTs stored in
what type of vesicles are neuropeptides stored in
small clear synaptic vesicles
large dense core vesicles
when does co-release of neuropeptides and NTs occur?
when there is a higher frequency of APs, the increase in [Ca2+] is more widespread in the terminal, so synaptic vesicles and neuropeptide vesicles are both exocytosed.
under what conditions does co-release of NT and neuropeptides not occur?
when there is a lower frequency of APs, the elevated Ca2+ levels are more local, resulting in only the exocytosis of NT vesicles
why does low frequency APs and local Ca2+ elevation only cause NT release rather than co release of NT and neuroptides?
because the NT synaptic vesicles are found closer to the membrane, the neuropeptide vesicles dont experience the elevated Ca2+ levels as they are further from the membrane
differences between NT transmission and neuropeptide transmission
neuropeptides can act across larger distances - distance between pre&post membranes in periphery is much longer than in the CNS
NPs are slower acting than NTs for this reason
what is neuormodulation (in regards to NPs)
can be presynaptic -> the released NP acts presynaptically to inhibit / increase release (of itself or the primary NT)
can be postsynaptic -> NP acts on post synaptic receptors to alter the primary response of the released NT
describe the effects of VIP and ACh in PNS nerves of salivary glands as an example of cotransmission / neuromodulation
- at low frequency of stimulation, response is normal ACh released acts on muscarinic receptors causing salivary secretion and minor vasodilation
- at high frequency of stimulation VIP is co-released with ACh which:
- presynaptically increases ACh release
- enhances post-synaptic response (increased vaodilation)
describe the effects of NPY and NA in SNS smooth muscle as an example of cotransmission / neuromodulation
- low frequency -> stimulation preferentially releases NA over NPY resulting in vasoconstriction via a1 receptors
- high frequency, intermittent stimulation is optimal for NPY release. which has the following effects:
low [NPY] potentiates NA induced vasoconstriction
high [NPY] acts on Y1 receptors (post synaptically) to cause vasoconstriction and acts on Y2 receptors (presynaptically) to inhibit NPY and NA via negative feedback
how are the effects of NA affected by low concenrtrations of NPY (co released)
NPY enhances the NA induced vasoconstriction
what effects do high [NPY] have (NA co release)
act on Y1 receptors post synaptically to cause vasoconstriction
act on Y2 receptors presynaptically to inhibit NPY and NA release from presynaptic terminal (negative feedback)
what is the optimal stimulation frequency for NPY release
high frequency, intermittent stimulation
do all peptide neurones also release a classic transmitter?
no
for example oxytocin is released from magnocellular neurones on its own
what are the effects of NPY
in PNS
in CNS
PNS
- potent vasoconstrictor via Y1 receptors of vascular smooth muscle
- analgesia via inhibition of SP and NKA release in dorsal horn via Y2 receptors
CNS
- stimulates feeding via Y1 and Y5
- its inhibitory effects make it a sedative (via Y1) and antiepileptic via Y2 (in neurones)
what type of receptors are ALL neuropeptide receptors
GPCRs
what are the NPY receptors called and what are they coupled to
Y receptors
Gi/o
describe how NPY causes vasoconstriction
- acts on Y1 receptors of vascular smooth muscle which can cause increase in intracellular [Ca2+]
- this causes vasoconstriction
explain why NPY activation of Y1 receptors can cause vasoconstriction, but also have sedative effects
Y1 recepotrs in different locations (smooth muscle vs neurones) have different effects
explain how NPY causes inhibition when binding to
Y1
Y2
receptors in CNS
binding to Y1 (post synaptic) causes opening of K+ channels -> hyperpolarisation
binding to y2 (pre synaptic) can block NT release or open Ca2+ channels
what are Neurokinin receptors coupled to?
Gq
how many NK receptors are there? name them
3
NK1-3
what NK receptor has the highest affinity for SP
NK1
NKA has the highest affinity for which NK receptor?
NK2
NKB has the highest affinity for which NK receptor?
NK3
what are the effects of NKR activation? (SP and NKA)
increase intracellular [Ca2+] in neuronal and non neuronal cells
so cause vasoconstriction
increase excitability in spinal cord (sensory NTs)
major sensory NTs in spinal cord and intestine
what are possible future therapeutics targetting Y receptors
y1 -> anti hypertensives, anti-epileptics,
Y5 -> anti-inflammatory
other Y receptors -> anti-inflammatory
describe a drug / therapeutic targeting NK receptors
NK1 antagonists are proven anti-emetics (aprepitant)
often used in chemotherapy to treat sickness
explain the use of DPPIV inhibitors
inhibition of aminopeptidase (DPPIV) increases the half life of GLP-1
GLP-1 increases glucose dependant insulin release and pancreatic B cell number
increasing its half life useful treatment in type 2 diabetes
