NEUROTRANSMITTERSandRECEPTORS

PhysiologyUnit2

InPhysiologyToday

AxonalTransport• Movementoforganelles,

othermaterialsfromonepartofthecelltoanother

• Microtubule“rails” thatrunthelengthofanaxon

• Motorproteins– Kinesins

• Antegrademovement

– Dyniens• Retrogrademovement

ReleaseofNeurotransmitter• AParrivesattheterminalendbulbofpre-synapticneuron

• Voltage-gatedCa2+channelsopen• Ca2+influxactivatescalmodulin• Activatedcalmodulinactivatesaproteinkinase• SeriesofeventsleadtoaconformationalchangeinSNAREproteins

• SNAREproteinsdockvesicles,vesiclesfusewiththepre-synapticmembraneandreleaseneurotransmitter

• NTbindstoreceptorsonpostsynapticmembrane

NeurotransmitterRelease

ActivationofthePostsynapticCell

SynapticIntegration

NeurotransmitterClearance• NTbindingtothereceptorisatransientevent• Unboundneurotransmitterinthesynapticcleftisclearedveryquickly1. Reuptake• Secondaryactivetransportbackintothepresynapticterminal

2. Activetransportintoastrocytes3. Diffuseawayfromthereceptortype4. Inactivatedbyanenzyme• Someoftheinactiveproductsaretransportedbackintothepresynapticneurontoberecycled

WhatisaNeurotransmitter?1. Thechemicalexistsinthepresynapticterminal2. Theenzymesforsynthesingthetransmitterexistinthe

presynapticterminalsor,inthecaseofpeptides,inthecellbody

3. Thetransmitterisreleasedwhennerveimpulsesreachtheterminals,andinsufficientquantitiestoproducenormalchangesinpostsynapticpotentials

4. Specificreceptorsexistonthepostsynapticmembraneforthereleasedtransmitter

5. Blockingreleaseofthetransmitterpreventspresynapticnerveimpulsesfromalteringtheactivityofthepostsynapticcell

NeurotransmittersandNeuromodulators

• Neurotransmitter– Achemicalmessengerreleasedbyaneuron– ElicitsanEPSPorIPSP

• Neuromodulators– Elicitcomplexresponses– Sometimessynthesizedandco-releasedwiththeNT– Canalsobehormones,paracrineagentsandcytokines– Modifythecell’sresponse

Receptors

• AmembraneproteinthathasabindingsiteforaNT

• 2kindsofreceptors– Ionotropic• Thereceptoristheionchannel

–Metabotropic• IndirectlyregulatesionchannelactivitybyactivatingaG-protein2nd messengersystem

Neurotransmitters

• QuaternaryAmine– Acetylcholine(ACh)

• Monoamines– Catecholamines

• Dopamine(DA)• Norepinephrine(NE)• Epinephrine(Epi)

– Serotonin(5-HT)• Derivedfromtryptophan

– Histamine• Derivedfromhistadine

• Aminoacids– GABA

• Inhibitory

– Glutamate• Excitatory

Acetylcholine(ACh)

• CholinergicneuronsreleaseACh• Synthesizedfromcholineandacetyl-CoA• AChisaneurotransmitterfoundinbothCNSandPNS

• Effectors– CNS:neurons– PNS:muscle

ActionsofAcetylcholine• CentralNervousSystem(CNS)

– Widespreadinthebrain(neuronsofthepons,thalamus,forebrain)– Neuromodulator

• Plasticity,arousal,reward– Sustainingattention– Decisionmaking

• PeripheralNervousSystem(PNS)– SomaticNervousSystem– ParasympatheticNervousSystem

• Releasedfrompreandpostganglionicneurons– SympatheticNervousSystem

• Releasedfrompreganglionicneurons

NicotinicAChReceptors• N-AChreceptors– Ionotropicreceptor– BindingofAChopensNa+ channel

– resultsinanEPSP

• Locations- Autonomicganglia- Skeletalmusclefibers

MuscarinicAChReceptors

• M-AChreceptors– Metabotropicreceptor– G-proteinopensK+ channel

– ResultsinanIPSP

• Locations– Smoothmuscle– Cardiacmuscle– Glands

ClearanceofAcetylcholine

• Degradedbyacetycholinesterase(AChe)

• DegradesunboundACh

• Reuptakeofcholine• Acetateclearedbydiffusion

Catecholamines• Dopamine,NorepinephrineandEpinephrine(*)• Involvedin:– Statesofconsciousness– Mood– Motivation– Directionalattention(focusing)– Movement– Bloodpressureregulation– Hormonerelease

CatecholaminesBiosynthesisPathway

Norepinephrine(NE)

• NoradrenergicneuronsreleaseNE• NEisaneurotransmitterfoundinbothCNSandPNS– CNS• Adrenergicneuronshavetheirnervecellbodiesinbrainstemandhypothalamus• Heavilybranchedaxons• Projecttothecerebralcortex,limbicsystem,thalamus,cerebellumandspinalcord

– PNS• Postganglionicneuronsofsympatheticnervoussystem

ActionsofNorepinephrine(NE)

• Responsibleforconcentration• Fightorflightresponse– Heartrate– Respiratoryrate– Freeupglucosereserves– Increaseinoxygenflowtothebrain– Increasebloodflowtoskeletalmuscle

• Increasesvasculartone

ReceptorsforNorepinephrine(NE)

• AdrenergicReceptors–Metabotropic(bothsubtypes)1. Alphaadrenergicreceptors2. Betaadrenergicreceptors

• AdrenergicreceptorscanbindtobothNEandEpi

• Effectors– Smoothmuscle– Cardiacmuscle– Glands

AdrenergicReceptors

• AlphaAdrenergicReceptors

• 2subtypes• α1– UseDAGandIP3 as2ndmessengers

– IncreasecytoplasmicCa2+ levels

• α2– InhibitscAMPas2ndmessenger

AdrenergicReceptors

• BetaAdrenergicReceptors

• 3subtypes– AllactivatecAMPasa2nd messenger

– β1– β2– Β3

ClearanceofNorepinephrineCatecholamines

• Presynaptic– Reuptake– DegradationbyMAO

• monoamineoxidase

• PostsynapticorCleft– DegradationbyCOMT

• Catechol-O-methyltransferase

Dopamine(DA)

• DopaminergicneuronsreleaseDA• DAisaneurotransmitterfoundintheCNS/PNS (digestion)• Dopamineisreleasedbyneuronsofthemidbrainandhypothalamus

ActionsofDA• Responsibleforalertness• Alsoinvolvedin:– Cognition(thinking)– Behavior(laughter,pleasure,

aggression,fear

– MotorActivity– MotivationandReward– Sleep– Mood– Attention– Learning

• MesolimbicDopamineSystem– Neuronsoriginateinmidbrain,sendaxonstolimbicsystem

– Involvedinmodulatingrewardbehaviorsuchas• Eating,sex,drugs

DiseasesandDisordersofDA

• Parkinson’sDisease– Deathofdopaminergicneuronsinthemidbrain

• Basalganglialocatedinthemidbrain• Basalgangliainvolvedininitiatingmotorprograms• LowlevelsofDAresultinstiffnessandgreatlyreducedmovement

• Addictivedrugs- Cocaine,nicotine,amphetamines

- HighlevelsofDAresultinhighlevelsofmotoractivityandimpulsivebehavior

- Adderall(ADD,ADHDmedication)- Inhibitre-uptakeofdopamine

DopamineReceptor

• Dopaminereceptorsareg-proteincoupledreceptorsthat(+)or(-)theproductionofcAMP

• Canbeinhibitoryorexcitatory

ClearanceofDopamineCatecholamines

• Presynaptic– Reuptake– DegradationbyMAO

• monoamineoxidase

• PostsynapticorCleft– DegradationbyCOMT

• Catechol-O-methyltransferase

Serotonin(5-HT)

• Serotonergicneuronsreleaseserotonin– Alsosecretedbycellsoutsideofthenervoussystemasahormone

• DerivedfromL-tryptophan(essentiala.a.)• SerotoninisaneurotransmitterfoundinbothCNSandPNS

ActionsofSerotonin

• DirectActions– Cognition– Aggression– Anxiety– Mood– Appetite– Sleep– Memory– Learning– Thermoregulation

• NeuromodulatorActions– Modulatethereleaseofneurotransmitters• Glutamate,GABA,DA,NE,ACh

– Modulatethereleaseofhormones• Epi,oxytocin,prolactin,ADH,cortisol,corticotropin,substanceP

ActionsofSerotonin• Undercircadiancontrol- Activityofserotonergicneuronsis• lowestorabsentduringsleep• highestduringstatesofalertwakefulness

• Involvedinregulating:digestion,aggression,appetite,addiction,bloodpressure,impulsiveness,memory,nausea,erection,orgasm,sleep,sociability,thermoregulation

• Maycontrolmood

DisordersofSerotonin

• Depression- Lowlevelsassociatedwithdepression– SSRI’s:selectiveserotoninreuptakeinhibitor

• medicationswhichinhibitthereuptakeofserotonin(Prozac,Paxil,Zoloft)

– MAOI’s:monoamineoxidaseinhibitor• Medicationsthatinhibitthereuptakeofmonoaminespresynaptically– IncludesNEandDA

• Alsoimplicatedinmigranes,psychosis,overeating,problemswithgastrointestinalmotility

SerotoninReceptors• Serotoninreceptorsare

called5-HTreceptors– mostly g-proteincoupled

receptorsthat(+)or(-)cAMP– Canbeexcitatoryor

inhibitory

• 14knownsubtypesof5-HTreceptors

• Effectors– NeuronsofCNS,PNS– Smoothmuscle(GItract,

bloodvessels)– Platelets

ClearanceofSerotonin

• Clearanceofserotoninisbyreuptake–Monoaminetransporterspecificforserotonin(5-HT)calledSERT (serotoninreuptaketransporter)

– SERT transportersarepresentinthepresynapticmembrane

vVariouschemicalscaninhibit5-HT reuptake–MDMA (ecstasy)– Amphetamines– Cocaine

Histamine

• HistaminergicneuronsreleaseHistamine• Derivedfromhistidine(essentiala.a.)• Histaminereleasedbyneuronsofthehypothalamusandprojecttothecortex–Modulatessleep

• HavethegreatestfiringpatternwhileawakethananyotherNTmeasured

ActionsofHistamine

• Actions(Many,many,many)–Motionsickness– Regulatesleep– Appetitesuppression– Involvedinforgettingmemoriesandthingslearned

– Alsohasmanyimmuneanddigestiveactions

HistamineReceptors

• HistaminereceptorsarecalledHTReceptors– 4subtypes

• Histaminereceptorsinthebrainaremostlyofthefollowing2types:– g-proteincoupledreceptorsthatactivateorinhibitDAGandIP3 as2nd messengers

– g-proteincoupledreceptorsthatinhibitK+channels

• Inhibitoryorexcitatoryeffects

ClearanceofHistamine

• Activetransportintoastrocytes

GABAgamma-Aminobutyricacid

• GABAergicneuronsreleaseGABA• Derivedfromglutamate• GABAisreleasedfromsmallinterneurons– Almostallpartsofthebrain– “fine-tunes” neurotransmission

• GABAisreleasedbyneuronsofthe:– Basalganglia(midbrain)– Hypothalamus– Centralgraymatter– Hippocampus

ActionsofGABA

• Regulatesmuscletone• Dampensskeletalmusclecontraction• Otherchemicals/drugscanbindtoGABAreceptorsGABAreceptors– EnhancestheeffectofGABA• Sedatives(barbiturates)• Musclerelaxers• Anti-anxietymedications(benzodiazepines:Xanax,Valium)

GABAReceptor

• GABAreceptors– Ionotropicreceptors– Cl- channels

• MajorinhibitoryNTproducedinCNS

ClearanceofGABA

• GABAisclearedbyactivetransportintoastrocytes

Glutamate

• Glutamergicneuronsreleaseglutamate–MostcommonexcitatoryNTinCNS– 90%ofsynapses

• Glutamateisreleasedbyneuronsofthe:– Cortex– Hippocampus– Basalganglia– Amygdala

GlutamateReceptors• NMDA receptors

– Ca2+ channel– ActivatesCa2+2nd

messengersystem• AMPA receptors

– ReceptorisaNa+ channel– Fast,common– Long-termpotentiation

• Ionotropic receptors• Involvedinmemoryand

learning

ClearanceofGlutamate

• Diffusion

• Clearedbyactivetransportintoastrocytes

NitricOxide(NO)

• Precursor:L-arginine• Rolesinte nervoussystem– NTusingcGMP assecondmessenger• PNS=smoothmusclerelaxation• CNS=memoryandlearning

Neuropeptides• 2ormoreaminoacidsboundtogether• Neuromodulators- Releasedinsmallamounts– Co-releasedwithotherNTs

• Mediatesensory(pain)andemotionalresponses• Examples– CCK=satiety– SubstanceP– Endogenousopioids

• Beta-endorphins• Oxytocin• Receptorsbindopiates(morphine,codeine)

PeripheralNervousSystemControl