Neuropeptides

Question 1

Peptide synthesis

Answer 1

Coded in genome -> prepropeptide -> propeptide -> neuropeptide and junk -> packages into secretory vesicles (dense-core vesicles) -> secreted in large bolus

Question 2

Pre-pro-peptide

Answer 2

Signal sequence -> endoplasmic reticulum -> propeptide via signal peptidase

Question 3

Pro-peptide

Answer 3

aa signals - basic Lys, Arg
Carboxypeptidases, PTMs, cathepsin L, Arg/Lys animopeptidase

Question 4

Neuropeptide diversity

Answer 4

Some pro-prepeptides have multiple copies of the same neuropeptide or multiple different
tissue specific processing (depends on enzymes)

Question 5

Neuropeptide function

Answer 5

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

Question 6

Neuropeptide Y

Answer 6

2 GPCR subtypes Y1 and Y2
Y1 - post synapse, inhibit hypocretin cell
Y2 - pre synapse, release GABA and glutamate

Question 7

Targeting of peptides

Answer 7

-Processing
-Release mechanism
-Modulate proteases or bind to peptide (mab)
-Receptor (agonist/antagonist, recombinant, variant, mab)

Question 8

Pain

Answer 8

Nociception - noxious peripheral stimuli
Acute or chronic

Question 9

Pain pathways

Answer 9

Body pain vs face/head pain
Body - dorsal root ganglia -> brain
Face - trigeminal ganglia -> brain
C fibres and A∂ fibres important

Question 10

Nociception

Answer 10

Input at free nerve endings
Thermal, mechanical and chemical stimuli
Glutamate = fast, neuropeptides = slow
Neuropathic pain - damage to neurons

Question 11

Neuropeptides in pain

Answer 11

Enhance nociception eg. CGRP and Substance P
Enhance inhibitory pathways to reduce pain eg. opioid peptides

Question 12

Opioid receptors

Answer 12

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

Question 13

Opioid analgesics

Answer 13

Morphine, codeine -> mu recetor
Synthetic mu opioid receptor agonists
Side effects - respiratory depression, euphoria, dependance, GI

Question 14

Biased ligands

Answer 14

G protein and arrestin signalling
Avoid arresting = avoid side effects
Oliceridine = approved

Question 15

Headache disorders

Answer 15

Primary vs secondary
Cranial neuralgias, facial pain, migraine, tension-type, cluster

Question 16

Migraine

Answer 16

Hypersensitivity to light, sound, smell, touch, nausea
Episodic - 15 + days per month
Opioids don’t work

Question 17

Migraine modulation

Answer 17

Trigeminal nerve from TG ganglia
C fibres and AF fibres
CGRP and Substance P

Question 18

CGRP

Answer 18

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

Question 19

Migraine drugs

Answer 19

Rimegepant - antagonist
Galcanezumab - antibody to peptide
Crenumab - antibody antagonist at receptor
Variable response

Question 20

PACAP

Answer 20

Elevated during migraine
Infusion - cause migraine attack
2 forms, complex receptors, dont know MoA