neurotransmitters and receptors - mt....
TRANSCRIPT
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NEUROTRANSMITTERSandRECEPTORS
PhysiologyUnit2
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InPhysiologyToday
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AxonalTransport• Movementoforganelles,
othermaterialsfromonepartofthecelltoanother
• Microtubule“rails” thatrunthelengthofanaxon
• Motorproteins– Kinesins
• Antegrademovement
– Dyniens• Retrogrademovement
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ReleaseofNeurotransmitter• AParrivesattheterminalendbulbofpre-synapticneuron
• Voltage-gatedCa2+channelsopen• Ca2+influxactivatescalmodulin• Activatedcalmodulinactivatesaproteinkinase• SeriesofeventsleadtoaconformationalchangeinSNAREproteins
• SNAREproteinsdockvesicles,vesiclesfusewiththepre-synapticmembraneandreleaseneurotransmitter
• NTbindstoreceptorsonpostsynapticmembrane
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NeurotransmitterRelease
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ActivationofthePostsynapticCell
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SynapticIntegration
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NeurotransmitterClearance• NTbindingtothereceptorisatransientevent• Unboundneurotransmitterinthesynapticcleftisclearedveryquickly1. Reuptake• Secondaryactivetransportbackintothepresynapticterminal
2. Activetransportintoastrocytes3. Diffuseawayfromthereceptortype4. Inactivatedbyanenzyme• Someoftheinactiveproductsaretransportedbackintothepresynapticneurontoberecycled
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WhatisaNeurotransmitter?1. Thechemicalexistsinthepresynapticterminal2. Theenzymesforsynthesingthetransmitterexistinthe
presynapticterminalsor,inthecaseofpeptides,inthecellbody
3. Thetransmitterisreleasedwhennerveimpulsesreachtheterminals,andinsufficientquantitiestoproducenormalchangesinpostsynapticpotentials
4. Specificreceptorsexistonthepostsynapticmembraneforthereleasedtransmitter
5. Blockingreleaseofthetransmitterpreventspresynapticnerveimpulsesfromalteringtheactivityofthepostsynapticcell
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NeurotransmittersandNeuromodulators
• Neurotransmitter– Achemicalmessengerreleasedbyaneuron– ElicitsanEPSPorIPSP
• Neuromodulators– Elicitcomplexresponses– Sometimessynthesizedandco-releasedwiththeNT– Canalsobehormones,paracrineagentsandcytokines– Modifythecell’sresponse
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Receptors
• AmembraneproteinthathasabindingsiteforaNT
• 2kindsofreceptors– Ionotropic• Thereceptoristheionchannel
–Metabotropic• IndirectlyregulatesionchannelactivitybyactivatingaG-protein2nd messengersystem
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Neurotransmitters
• QuaternaryAmine– Acetylcholine(ACh)
• Monoamines– Catecholamines
• Dopamine(DA)• Norepinephrine(NE)• Epinephrine(Epi)
– Serotonin(5-HT)• Derivedfromtryptophan
– Histamine• Derivedfromhistadine
• Aminoacids– GABA
• Inhibitory
– Glutamate• Excitatory
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Acetylcholine(ACh)
• CholinergicneuronsreleaseACh• Synthesizedfromcholineandacetyl-CoA• AChisaneurotransmitterfoundinbothCNSandPNS
• Effectors– CNS:neurons– PNS:muscle
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ActionsofAcetylcholine• CentralNervousSystem(CNS)
– Widespreadinthebrain(neuronsofthepons,thalamus,forebrain)– Neuromodulator
• Plasticity,arousal,reward– Sustainingattention– Decisionmaking
• PeripheralNervousSystem(PNS)– SomaticNervousSystem– ParasympatheticNervousSystem
• Releasedfrompreandpostganglionicneurons– SympatheticNervousSystem
• Releasedfrompreganglionicneurons
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NicotinicAChReceptors• N-AChreceptors– Ionotropicreceptor– BindingofAChopensNa+ channel
– resultsinanEPSP
• Locations- Autonomicganglia- Skeletalmusclefibers
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MuscarinicAChReceptors
• M-AChreceptors– Metabotropicreceptor– G-proteinopensK+ channel
– ResultsinanIPSP
• Locations– Smoothmuscle– Cardiacmuscle– Glands
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ClearanceofAcetylcholine
• Degradedbyacetycholinesterase(AChe)
• DegradesunboundACh
• Reuptakeofcholine• Acetateclearedbydiffusion
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Catecholamines• Dopamine,NorepinephrineandEpinephrine(*)• Involvedin:– Statesofconsciousness– Mood– Motivation– Directionalattention(focusing)– Movement– Bloodpressureregulation– Hormonerelease
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CatecholaminesBiosynthesisPathway
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Norepinephrine(NE)
• NoradrenergicneuronsreleaseNE• NEisaneurotransmitterfoundinbothCNSandPNS– CNS• Adrenergicneuronshavetheirnervecellbodiesinbrainstemandhypothalamus• Heavilybranchedaxons• Projecttothecerebralcortex,limbicsystem,thalamus,cerebellumandspinalcord
– PNS• Postganglionicneuronsofsympatheticnervoussystem
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ActionsofNorepinephrine(NE)
• Responsibleforconcentration• Fightorflightresponse– Heartrate– Respiratoryrate– Freeupglucosereserves– Increaseinoxygenflowtothebrain– Increasebloodflowtoskeletalmuscle
• Increasesvasculartone
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ReceptorsforNorepinephrine(NE)
• AdrenergicReceptors–Metabotropic(bothsubtypes)1. Alphaadrenergicreceptors2. Betaadrenergicreceptors
• AdrenergicreceptorscanbindtobothNEandEpi
• Effectors– Smoothmuscle– Cardiacmuscle– Glands
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AdrenergicReceptors
• AlphaAdrenergicReceptors
• 2subtypes• α1– UseDAGandIP3 as2ndmessengers
– IncreasecytoplasmicCa2+ levels
• α2– InhibitscAMPas2ndmessenger
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AdrenergicReceptors
• BetaAdrenergicReceptors
• 3subtypes– AllactivatecAMPasa2nd messenger
– β1– β2– Β3
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ClearanceofNorepinephrineCatecholamines
• Presynaptic– Reuptake– DegradationbyMAO
• monoamineoxidase
• PostsynapticorCleft– DegradationbyCOMT
• Catechol-O-methyltransferase
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Dopamine(DA)
• DopaminergicneuronsreleaseDA• DAisaneurotransmitterfoundintheCNS/PNS (digestion)• Dopamineisreleasedbyneuronsofthemidbrainandhypothalamus
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ActionsofDA• Responsibleforalertness• Alsoinvolvedin:– Cognition(thinking)– Behavior(laughter,pleasure,
aggression,fear
– MotorActivity– MotivationandReward– Sleep– Mood– Attention– Learning
• MesolimbicDopamineSystem– Neuronsoriginateinmidbrain,sendaxonstolimbicsystem
– Involvedinmodulatingrewardbehaviorsuchas• Eating,sex,drugs
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DiseasesandDisordersofDA
• Parkinson’sDisease– Deathofdopaminergicneuronsinthemidbrain
• Basalganglialocatedinthemidbrain• Basalgangliainvolvedininitiatingmotorprograms• LowlevelsofDAresultinstiffnessandgreatlyreducedmovement
• Addictivedrugs- Cocaine,nicotine,amphetamines
- HighlevelsofDAresultinhighlevelsofmotoractivityandimpulsivebehavior
- Adderall(ADD,ADHDmedication)- Inhibitre-uptakeofdopamine
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DopamineReceptor
• Dopaminereceptorsareg-proteincoupledreceptorsthat(+)or(-)theproductionofcAMP
• Canbeinhibitoryorexcitatory
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ClearanceofDopamineCatecholamines
• Presynaptic– Reuptake– DegradationbyMAO
• monoamineoxidase
• PostsynapticorCleft– DegradationbyCOMT
• Catechol-O-methyltransferase
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Serotonin(5-HT)
• Serotonergicneuronsreleaseserotonin– Alsosecretedbycellsoutsideofthenervoussystemasahormone
• DerivedfromL-tryptophan(essentiala.a.)• SerotoninisaneurotransmitterfoundinbothCNSandPNS
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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
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ActionsofSerotonin• Undercircadiancontrol- Activityofserotonergicneuronsis• lowestorabsentduringsleep• highestduringstatesofalertwakefulness
• Involvedinregulating:digestion,aggression,appetite,addiction,bloodpressure,impulsiveness,memory,nausea,erection,orgasm,sleep,sociability,thermoregulation
• Maycontrolmood
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DisordersofSerotonin
• Depression- Lowlevelsassociatedwithdepression– SSRI’s:selectiveserotoninreuptakeinhibitor
• medicationswhichinhibitthereuptakeofserotonin(Prozac,Paxil,Zoloft)
– MAOI’s:monoamineoxidaseinhibitor• Medicationsthatinhibitthereuptakeofmonoaminespresynaptically– IncludesNEandDA
• Alsoimplicatedinmigranes,psychosis,overeating,problemswithgastrointestinalmotility
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SerotoninReceptors• Serotoninreceptorsare
called5-HTreceptors– mostly g-proteincoupled
receptorsthat(+)or(-)cAMP– Canbeexcitatoryor
inhibitory
• 14knownsubtypesof5-HTreceptors
• Effectors– NeuronsofCNS,PNS– Smoothmuscle(GItract,
bloodvessels)– Platelets
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ClearanceofSerotonin
• Clearanceofserotoninisbyreuptake–Monoaminetransporterspecificforserotonin(5-HT)calledSERT (serotoninreuptaketransporter)
– SERT transportersarepresentinthepresynapticmembrane
vVariouschemicalscaninhibit5-HT reuptake–MDMA (ecstasy)– Amphetamines– Cocaine
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Histamine
• HistaminergicneuronsreleaseHistamine• Derivedfromhistidine(essentiala.a.)• Histaminereleasedbyneuronsofthehypothalamusandprojecttothecortex–Modulatessleep
• HavethegreatestfiringpatternwhileawakethananyotherNTmeasured
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ActionsofHistamine
• Actions(Many,many,many)–Motionsickness– Regulatesleep– Appetitesuppression– Involvedinforgettingmemoriesandthingslearned
– Alsohasmanyimmuneanddigestiveactions
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HistamineReceptors
• HistaminereceptorsarecalledHTReceptors– 4subtypes
• Histaminereceptorsinthebrainaremostlyofthefollowing2types:– g-proteincoupledreceptorsthatactivateorinhibitDAGandIP3 as2nd messengers
– g-proteincoupledreceptorsthatinhibitK+channels
• Inhibitoryorexcitatoryeffects
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ClearanceofHistamine
• Activetransportintoastrocytes
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GABAgamma-Aminobutyricacid
• GABAergicneuronsreleaseGABA• Derivedfromglutamate• GABAisreleasedfromsmallinterneurons– Almostallpartsofthebrain– “fine-tunes” neurotransmission
• GABAisreleasedbyneuronsofthe:– Basalganglia(midbrain)– Hypothalamus– Centralgraymatter– Hippocampus
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ActionsofGABA
• Regulatesmuscletone• Dampensskeletalmusclecontraction• Otherchemicals/drugscanbindtoGABAreceptorsGABAreceptors– EnhancestheeffectofGABA• Sedatives(barbiturates)• Musclerelaxers• Anti-anxietymedications(benzodiazepines:Xanax,Valium)
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GABAReceptor
• GABAreceptors– Ionotropicreceptors– Cl- channels
• MajorinhibitoryNTproducedinCNS
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ClearanceofGABA
• GABAisclearedbyactivetransportintoastrocytes
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Glutamate
• Glutamergicneuronsreleaseglutamate–MostcommonexcitatoryNTinCNS– 90%ofsynapses
• Glutamateisreleasedbyneuronsofthe:– Cortex– Hippocampus– Basalganglia– Amygdala
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GlutamateReceptors• NMDA receptors
– Ca2+ channel– ActivatesCa2+2nd
messengersystem• AMPA receptors
– ReceptorisaNa+ channel– Fast,common– Long-termpotentiation
• Ionotropic receptors• Involvedinmemoryand
learning
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ClearanceofGlutamate
• Diffusion
• Clearedbyactivetransportintoastrocytes
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NitricOxide(NO)
• Precursor:L-arginine• Rolesinte nervoussystem– NTusingcGMP assecondmessenger• PNS=smoothmusclerelaxation• CNS=memoryandlearning
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Neuropeptides• 2ormoreaminoacidsboundtogether• Neuromodulators- Releasedinsmallamounts– Co-releasedwithotherNTs
• Mediatesensory(pain)andemotionalresponses• Examples– CCK=satiety– SubstanceP– Endogenousopioids
• Beta-endorphins• Oxytocin• Receptorsbindopiates(morphine,codeine)
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PeripheralNervousSystemControl