Neuropeptides Flashcards
Peptide synthesis
Coded in genome -> prepropeptide -> propeptide -> neuropeptide and junk -> packages into secretory vesicles (dense-core vesicles) -> secreted in large bolus
Pre-pro-peptide
Signal sequence -> endoplasmic reticulum -> propeptide via signal peptidase
Pro-peptide
aa signals - basic Lys, Arg
Carboxypeptidases, PTMs, cathepsin L, Arg/Lys animopeptidase
Neuropeptide diversity
Some pro-prepeptides have multiple copies of the same neuropeptide or multiple different
tissue specific processing (depends on enzymes)
Neuropeptide function
Neuromodulators - can diffuse and act past synapse
High receptor affinity, have an effect at low concentration
Can act pre and post synaptically
No reuptake, just proteases = slow
GPCRs
Neuropeptide Y
2 GPCR subtypes Y1 and Y2
Y1 - post synapse, inhibit hypocretin cell
Y2 - pre synapse, release GABA and glutamate
Targeting of peptides
-Processing
-Release mechanism
-Modulate proteases or bind to peptide (mab)
-Receptor (agonist/antagonist, recombinant, variant, mab)
Pain
Nociception - noxious peripheral stimuli
Acute or chronic
Pain pathways
Body pain vs face/head pain
Body - dorsal root ganglia -> brain
Face - trigeminal ganglia -> brain
C fibres and A∂ fibres important
Nociception
Input at free nerve endings
Thermal, mechanical and chemical stimuli
Glutamate = fast, neuropeptides = slow
Neuropathic pain - damage to neurons
Neuropeptides in pain
Enhance nociception eg. CGRP and Substance P
Enhance inhibitory pathways to reduce pain eg. opioid peptides
Opioid receptors
DOPR, KOPR, NOPR, MOPR
Found in brain relevant to pain modulation
reduce nociception via stopping Ca2+ influx and cAMP
Post synapse = hyperpolarisatio, decrease signal transduction
Opioid analgesics
Morphine, codeine -> mu recetor
Synthetic mu opioid receptor agonists
Side effects - respiratory depression, euphoria, dependance, GI
Biased ligands
G protein and arrestin signalling
Avoid arresting = avoid side effects
Oliceridine = approved
Headache disorders
Primary vs secondary
Cranial neuralgias, facial pain, migraine, tension-type, cluster
Migraine
Hypersensitivity to light, sound, smell, touch, nausea
Episodic - 15 + days per month
Opioids don’t work
Migraine modulation
Trigeminal nerve from TG ganglia
C fibres and AF fibres
CGRP and Substance P
CGRP
37 aas, disulphide bond, C terminal amide
Sensory neurons (TG, brain stem)
1 gene -> multiple peptids (calcitonin OR CGPR)
Gas receptor - increase cAMP, increase neuronal excitability
CLR calcitonin-like receptor
Migraine drugs
Rimegepant - antagonist
Galcanezumab - antibody to peptide
Crenumab - antibody antagonist at receptor
Variable response
PACAP
Elevated during migraine
Infusion - cause migraine attack
2 forms, complex receptors, dont know MoA
