Neuropeptides Flashcards
What are the basic properties of neuropeptides?
Synthesised as large precursors in cell soma and transportd to release sites in LDCVs (large dense core).
-NPs are not recycled or reuptaken, only replenished through re-synthesis.
NPs are co-released with classical NTs.
Act on GPCRs to modulate/mediate neuronal communication BUT do not require point-to-point synaptic connections.
Can trigger complex coordinated behaviours.
Terminated by extracellular proteases/diffusion.
What are the generic actions of NPs?
Expresed and released by neurones to mediate/modulate neuronal communication.
Neuronal signalling molecules to influence particular brain functions like analgesia, reward…
Typically co-released with NTs.
Some NPs act as neurohormones produced in hypothalamus and act in peripheral tissues = ADH!!!!
Others are neuronal only.
Interesting facts about NPs?
NP signalling believed to have been established before small molecule NTs…
Used widely by coral, Hydra, Jelly fish.
100 different neuropeptides identified in mammalian brain - but only 90 genes encode precursors.
= some NPs emerge from same precursors, but are processed differently…
= e.g enkephalins derived from same Pre-proenkephalin A precursor.
How do NPs and small molecule NTs compare?
Vesicular conc. of NPs is much lower ~10mM compared to 100mM for NTs.
GPCR for NPs have much higher affinity ~ nM-uM range vs uM~mM…
Almost exclusively GPCRs - e.g V1 for ADH.
Release of NPs requires more intense stimulus and an initially more Ca2+ entry, ultimately requires less Ca2+ conc. overall…
- NP vesicles aren’t as tightly localised to Ca2+ channels as NTs are in microdomains..
Synthesised in soma and processed during trafficking vs local synthesis!
Can be released extra-synaptically.
= High frequency/burst firing required to trigger release in somatic, dendritic + extrasynaptic release.
Requires extracellular proteases/diffusion to terminate actions as opposed to dedicated degradative enzymes.
What can trigger release of NPs?
Can be released extra-synaptically.
= High frequency/burst firing required to trigger release in somatic, dendritic + extrasynaptic release.
More diffuse vessicle distribution, so not dependent on microdomains.
Release of NPs requires more intense stimulus and an initially more Ca2+ entry, ultimately requires less Ca2+ conc. overall…
- NP vesicles aren’t as tightly localised to Ca2+ channels as NTs are in microdomains..
What controls the expression and synthesis of NPs?
Factors which control rates of transcription of pro-peptide gene transcription + translation, secretion + degradation…
Extracellular proteases/diffusion terminated.
Expression regulated at several levels over different time scales.
Associated with slower, modulatory signalling as opposed to rapid synaptic transmission.
What are the major neuropeptides of mammals?
Substance P - sensory function/ pain - CNS..
Neurotensin - association with dopaminergic system, GI tract + CNS!
Oxytocin - hypothalamus to posterior pituitary
ADH = hypothalamus to posterior pituitary
met-enkephalin = opioid analgesic
alpha-endorpin. = opioid analgesic
General info about neuropeptide precursors?
Over 100 NPs identified in mammalian brain, over 90 different genes encoding precursors…
- predicted to be many more that have yet been identified.
NP are synthesised from much larger precursors atleast 90 AAs long.
Processing + PTM typically involves removal of signal sequence (localisation signal) cleavage events during trafficking = DURING AXONAL TRAFFICKING
A single precursor can give rise to multiple bioactive NPs, such as pre-proenkephalin A…
What is Substance P?
Co-released from terminals of C fibres/primary afferent sensory neurones responding to painful stimulation.
ALONGSIDE GLUTAMATE!!!!
Substance P activates Neurokinin 1 receptor.
= NK1 signalling.
NK1 activation triggers long-lasting depolarisation.
Wind up of dorsal horn neurones in spinal cord in respond to co-transmission of substance P (and CGRP) and glutamate.
Summation of long-lasting depolarisation from Substance P/CGRP believed to relieve Mg2+ block of NMDA receptors in a cumulative manner with successive stimuli.
= WIND UP SENSORY NEURONES!!!
How are Nps processed?
Processing + PTM typically involves removal of signal sequence (localisation signal) cleavage events during trafficking = DURING AXONAL TRAFFICKING
= Enzymes for processing a re co-localised in the LDCVs!
How are NP signalling terminated?
Not very specifically.
BNP - via Neprilysin…
ACE in lungs…
AMinopeptidase?
Aminopeptidase A for Ang III in the brain…
What are the endogenous opioids?
enkephalins are functional pentapeptides. (5 AA long)
= Leu and Met enkephalin.
and longer pepeptides called endorphins
= Alpha, B, Y. endorpin…
as well as Dynorphins…
Widely distributed in the brain but enkephalins and endorphins are not co-localised to same neurones!!!!
= Tissue specific processing gives rise to different opioids.
- differnent precursors..
Opioids all have the same N-terminal characteristic sequence.
Tyr-Gly-Gly-Phe-
What are the precursors of enkephalins and endorphins?
Enkephalins are derived from different pre-propeptides as endorphins.
Enkephalins, Leu and Met, are derived from pro-prenkephalin A!
What are the opioid receptors?
Dynorphin = kappa receptors.
Delta = leu-enkephalin.
MU = alpha-endorphin and met-enkephalin!!
= Gi/Go coupled, 7 TM recetors..
But also GP independent signalling pathways via arrestin, ERK, JNK signalling too.
How does dynorphin work?
Dynorphin can be released and acts in retrograde signalling to regulate further NT release from pre-synaptic neurone.
Via kappa receptors!!
