overview of neuropeptides: awakening the senses? · what are neuropeptides? • distinction between...
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Neuropeptides!
OverviewofNeuropeptides:AwakeningtheSenses?
AndrewRusso,PhDMolecularPhysiology&Biophysics
UniversityofIowa
DisclosuresFunding:NIH,DoD,VAMC,AlderBiopharma
Consultant:PharmnovoAlderBiopharmaEliLillyLeClairRyan;Medacorp;Sudler NY;DDBRemedy
Objectives
• Toappreciatethediversityofneuropeptidesinthebody.
• TorecognizethatneuropeptidesactbymodulatingsynaptictransmissionintheCNS.
• Toappreciatethatneuropeptidesalsoactinperipheraltissuestoaltercellularactivities.
http://www.luminousself.com/awakening-the-luminous-self.html
WhatareNeuropeptides?
• Distinctionbetweenneuropeptide andpeptidehormoneissolelybasedonsynthesisinneuron
• Botharesynthesized,modified,anddegradedbysamesetsofenzymesandbothcanactnearbyandatadistance
• Nearlyallneuropeptidesalsofoundaspeptidehormones
• So,whileweusethetermneuropeptide,remember…
• neuropeptidesarenotjustinthenervoussystem–theyactbothinandoutoftheCNS
CandacePert1946-2013http://www.6seconds.org/wp-content/uploads/2007/01/synapse-widened-pert.jpg
“Neuropeptides aresmallprotein-likemolecules(peptides)usedbyneurons tocommunicatewitheachother”(Wikipedia)
DiversityofNeuropeptides
• >100knownneuropeptidesinhumanbrainwww.neuropeptides.nl/tabel%20neuropeptides%20linked.htm
• >1000totalpeptidesinHomosapiens• basedongenomehomologiesofneuropeptides,peptidehormones,cytokines,growthfactors,antimicrobialpeptides,toxins&venompeptides,antifreezeproteins. www.peptides.be/?p=home
• Evolutionaryconservationofpeptidesandreceptors Global view of the evolution and diversity of
metazoan neuropeptide signaling Jekely, 2014 PNAS 110, 8702http://www.pnas.org/content/110/21/8702.full
DiverseNeuropeptideFamiliesConnected tomigraine? Other familiesCGRP:CGRP(a,b),calcitonin,amylin,adrenomedullin (AM1,2) Opioids:enkephalins,dynorphin,endorphins,nociceptin
Somatostatin/cortistatin
Glucagon/secretin:PACAP,VIP,glucagon,secretin,GHRH,GIP Natriureticfactors:ANF,BNF,CNP
GRP,neuromedins
Vasopressin/oxytocin Endothelins
CCK/gastrin
F- andY-amides:NPY,PPY,NPFF Insulins:insulin,IGFs,relaxins
Motilin/ghrelin
Tachykinins:SubP,neurokininA,neuropeptideK,neuropeptidegamma
Galanins
Gonadotropinreleasinghormones
Tensins:angiotensin,neurotensin,bradykinin NeuropeptideB/W/S
Neurexophilins
CRH-related:CRH,urocortin,urotensin Cerebellins
Granins:chromogranins,secretogranins
Adiposeneuropeptides:leptin,adiponectin,resistins
Family-less:orexins, MCH,TRH,PTHrP,CART,AGRP,prolactin,diazepam-bindinginhibitorpeptide,etc http://www.neuropeptides.nl/tabel%20neuropeptides%20linked.htm
CommonFeaturesofNeuropeptides
1. Modulatetargetcells• CNS=enhance/dampensynapticactivity• Peripheraltissues=neurohormones,manytargets,manyfunctions
2. Allaresignaltransducersthatactatcell-surfacereceptors• NearlyallactatGproteincoupledreceptors• Consistentwithneuropeptidesinducingaslowerandmodulatoryresponsecomparedtoneurotransmitters
3. Allprocessedfromprecursors• Synthesistodegradationsharedfeatures
CommonFeatures:Synthesis&Release
DickMains&BettyEipper labhttp://neuropeptidelab.uchc.edu
Processingofprecursors
Fromdensecorevesiclesatsynapses,cellbodies,varicositiesalongaxon.Atsynapsesoftenco-releasedwithaneurotransmitter.
Pro-peptidesareproteolytically cleavedandoftenmodifiedbyC-terminalamidation.
Howmanyneuropeptidesinavesicle?
• Howmanyneuropeptidescandanceontheheadofapin(orinasecretoryvesicle)?
• About100,000peptidesinalargedensecorevesicle
• Calculatedfrom:(3-10mM,Mains+Eipper,1999,BasicNeurochemistry,6th ed;60mM foroxytocin,vasopressininposteriorpit,Nordmann +Morris,1984,PNAS81:180-84)
• 100-200nmdiameter,vol =2x106 cubicnm,2x10-18 liter/vesicle• 10mmol/lx2x10-18 l=20x10-18 mmol =2x10-20 mol/vesicle• 2x10-20 mol x6x1023 molec/mol=1.2x104 molec/vesicle(~100,000peptides/vesicle)
• Tenstohundredsofvesiclesreleasedatsynapse,cellbodies,varicositiesintimescaleofmsec (chromaffincellshave20,000densecorevesicles,Plattner,JCB,1997)
• Somillionsofneuropeptidesarereleasedinashortburstfromasinglecell
CommonFeatures:Diffusion&Degradation
• Neuropeptidesdiffusefrompointofrelease(volumetransmission)
• Nonsynaptic dispersioninextracellularfluidandCSF• Slowlyremovedfromextracellularspace,whichcontributestorelativelylonglastingeffects
• Noreuptakesystem• Canbeactiveatrelativelylargedistancesatrelativelylowconcentrations
• Highreceptoraffinities(comparedtoneurotransmitters)
• Inactivationoccursbyextracellularproteases• Thiscanalsocreatedifferentbioactivepeptides
VandenPol(2012)Neuron76:98–115
Neuropeptides&SensoryPerception?
• Neuromodulationinthebraincoupledwithalteredperipheralsignals
http://www.epainassist.com/brain/sensory-processing-disorder-spd
http://www.luminousself.com/awakening-the-luminous-self.html
http://neuroscience.uth.tmc.edu/s1/chapter14.html
WithintheBrain:Neuromodulation• Generallymodulateactivityofco-releasedneurotransmitterstoeitherincreaseor
decreasestrengthofsynapticsignaling• Influencemanyfunctions,e.g.analgesia,reward,foodintake,metabolism,reproduction,
socialbehaviors,learningandmemory.
WithinthePeriphery:AlterCellularActivities
• Canfunctionsimilartopeptidehormonesandactonvarioustargettissuestomodulatenearlyallbodilyfunctions
• Atthevasculature
Edvinsson and Uddman, Brain Research Reviews 48(3):438-56 2005
NeuropeptideFamilies&MigraineConnected tomigraine? Other families
CGRP:CGRP (a,b),calcitonin,amylin,adrenomedullin (AM1,2) Opioids:enkephalins,dynorphin,endorphins,nociceptin
Somatostatin/cortistatin
Glucagon/secretin:PACAP,VIP,glucagon,secretin,GHRH,GIP
Natriureticfactors:ANF,BNF,CNP
GRP,neuromedins
Vasopressin/oxytocin Endothelins
CCK/gastrin
F- andY-amides:NPY,PPY,NPFF Insulins:insulin,IGFs,relaxins
Motilin/ghrelin
Tachykinins:SubP,neurokininA,neuropeptideK,neuropeptidegamma
Galanins
Gonadotropinreleasinghormones
Tensins:angiotensin,neurotensin,bradykinin NeuropeptideB/W/S
Neurexophilins
CRH-related:CRH,urocortins,urotensins Cerebellins
Granins:chromogranins,secretogranins
Adiposeneuropeptides:leptin,adiponectin,resistins
Family-less:orexins, MCH,TRH,PTHrP,,CART,AGRP,prolactin,diazepam-bindinginhibitorpeptide,etc http://www.neuropeptides.nl/tabel%20neuropeptides%20linked.htm
NPY:PremonitoryPhaseFeedingPeptides&Migraine
• NPY Roles- Pain- Appetite control- Synchronization of circadian rhythm
• NPY brain location- Hypothalamic nuclei- Basal ganglia- Limbic system
• NPY receptors (G protein coupled Y receptors)- Six sub-types- Not all in humans (1-5)
• In migraine- Could neuropeptide Y mechanisms link altered appetite and nociceptive processing?
SlidemodifiedfromPeterGoadsby
NPY &Trigeminovascular System
Martins-Oliveira et al.,Pain 2016;167:1666
• Anesthetized rat; durovascular stimulation• Recording from second order trigeminocervical neurons• NPY dose-dependently inhibits nociceptive trigeminovascular transmission
SlidefromPeterGoadsby
CRH&Migraine?
Robertetal.,2013,JNeurosci 33:8827Noseda andBurstein,2013,Pain154:S44 Lietal.,2016,Cell167:60
• CRHisastresshormonereleasedbythePVH,whichsendsprojectionstospinaltrigeminalnucleus
• Sexualdimorphism.CRHlevelsinPVHaretwiceashighinfemale&actionsareinhibitedbyoxytocininmales,butnotfemales
CRHlinkswithCGRPandPACAP
• CGRPinjectioninPVHinducesCRH-dependentreleaseofACTH,corticosterone• PACAPinjectioninPVHactivatesspinaltrigeminalnucleus
Robertetal.,2013,JNeurosci 33:8827
CGRPinjection
Dhillo etal.,2003,Endocrinology144:1420
PACAPinjection
Conclusion
• GiventheevidenceforCGRPandtheemergingevidenceforotherpeptides…
• Itseemslikelythatalteredneuropeptideactionsmaybeageneralthemeunderlyingtheheightenedsensorystateofmigraine http://io9.gizmodo.com/5752351/zapp
ing-the-brain-sparks-bright-ideas
Adisa KuburasBrandon ReaBianca MasonLevi SowersAnne-Sophie WattiezConnor CastonguayBennett Robertson
Collaborators:• Randy Kardon (U Iowa)• Pieter Poolman (U Iowa)• Leon Garcia-Martinez (Alder)• Minyan Wang (Xi’an Jiaton-
Liverpool Univ)• Mark Chapleau (U Iowa)
Former membersPaul DurhamAna RecoberEric Kaiser
Acknowledgments
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