Upload
others
View
8
Download
0
Embed Size (px)
Citation preview
NEUROTRANSMITTERSandRECEPTORS
PhysiologyUnit2
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)
– Serotonin(5-HT)• Derivedfromtryptophan
– Histamine• Derivedfromhistadine
• Aminoacids– GABA
• Inhibitory
– Glutamate• Excitatory
Acetylcholine(ACh)
• CholinergicneuronsreleaseACh• Synthesizedfromcholineandacetyl-CoA• AChisaneurotransmitterfoundinbothCNSandPNS
• Effectors– CNS:neurons– PNS:muscle,autonomicnerves,glands
ActionsofAcetylcholine
CentralNervousSystemCNSneuronstoCNSNeuron
– Widespreadinthebrain(pons,thalamus,forebrain)
– Sustainingattention– Decisionmaking– Neuromodulator
• Plasticity,arousal,reward
PeripheralNervousSystemPNS Neurons
toPNS Neurons,Muscle,Glands
– SomaticNervousSystem– ParasympatheticNervous
System• 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(arousal)– Mood– Motivation– Directionalattention(focusing)– Movement– Bloodpressureregulation– Hormonerelease
CatecholaminesBiosynthesisPathway
Norepinephrine(NE)
• NoradrenergicneuronsreleaseNE• NEisaneurotransmitterfoundinbothCNSandPNS– CNS• Adrenergicneuronshavetheirnervecellbodiesinbrainstemandhypothalamus• Heavilybranchedaxons• Projecttothecortex,limbicsystem,thalamus,cerebellumandspinalcord
– PNS• Postganglionicneuronsofsympatheticnervoussystem
ActionsofNorepinephrine(NE)
• Directionalattention(focus,concentration)• Fightorflightresponse– Heartrate– Respiratoryrate– Freeupglucosereserves– Increaseinoxygenflowtothebrain– Increasebloodflowtoskeletalmuscle
• Increasesvasculartone(vasoconstriction)
ReceptorsforNorepinephrine(NE)
• AdrenergicReceptors–Metabotropic(bothsubtypes)1. Alphaadrenergicreceptors(2subtypes)2. Betaadrenergicreceptors(3subtypes)
• 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
MAOMono-AmineOxidase
• Ifsomethingendsin“ase”– whatisit?
• WhatdoesMAOdo?– Oxidizesamonoamine
(DA/NE)• Whereisthisenzyme
located?• Couldthisenzyme
preventre-uptake?• So,howcananMAOI
increaseneurotransmission???
Dopamine(DA)
• DopaminergicneuronsreleaseDA• DAisaneurotransmitterfoundintheCNS/PNS (digestion)• Dopamineisreleasedbyneuronsofthemidbrainandhypothalamus
ActionsofDA
• Responsibleforalertness• Alsoinvolvedin:– Cognition(thinking)– Behavior(laughter,pleasure,
aggression,fear
– MotorActivity– MotivationandReward– Sleep– Mood– Attention– Learning
• MesolimbicDopamineSystem– Involvedinmodulatingrewardbehaviorsuchas• Eating,sex,drugs
– Dopaminergicneuronsoriginateinmidbrain,sendaxonstolimbicsystem
Low-LevelsofDA
• Parkinson’sDisease– Deathofdopaminergicneuronsinthemidbrain• Basalganglialocatedinthemidbrain
• Basalgangliainvolvedininitiatingmotorprograms
• LowlevelsofDAresultinstiffnessandgreatlyreducedmovement
• Alzheimer’sDisease
HighLevelsofDA
• DrugsthatincreaselevelsodDA:Addictivedrugs- Cocaine,nicotine,amphetamines
- HighlevelsofDAresultinhighlevelsofmotoractivityandimpulsivebehavior
- Adderall(ADD,ADHDmedication)- Inhibitre-uptakeofdopamine
DopamineReceptors
• Dopaminereceptorsareg-proteincoupledreceptorsthat(+)or(-)theproductionofcAMP
• Canbeinhibitoryorexcitatory
DopamineReceptorsElevatedDALevels
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
• Lowlevelsofserotoninareassociatedwith:– Depression– Migraineheadaches– Psychosis– Overeating– Problemswithgastrointestinalmotility
• Medicationstoincreaseneurotransmission– increasetheamountofactive
NT
• SSRI:SelectiveSerotoninReuptakeInhibitor– medicationswhichinhibitthe
reuptakeofserotonin(Prozac,Paxil,Zoloft)
• MAOI:MonoamineOxidaseInhibitor– Medicationthatinhibitthe
oxidationofthemonoamine
SerotoninReceptors
• Serotoninreceptorsarecalled5-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
vVariousrecreationaldrugsinhibit5-HTreuptake–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