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Psych 181: Dr. AnagnostarasPsych 181: Dr. Anagnostaras
Lecture 5Lecture 5
Synaptic TransmissionSynaptic Transmission
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Introduction to synaptic transmissionIntroduction to synaptic transmission
SynapsesSynapses(Gk., to clasp or join)(Gk., to clasp or join)
Site of action of most Site of action of most psychoactive drugspsychoactive drugs
6.5
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SynapsesSynapses
Know basic terminology:Know basic terminology: SomaSoma AxonAxon DendriteDendrite Synaptic vesiclesSynaptic vesicles Synaptic cleftSynaptic cleft PostsynapticPostsynaptic PresynapticPresynaptic GliaGlia
6.2
1
2 4
56
8
7 3
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SynapsesSynapses
Dendrites & Dendrites & spinesspines
3.10
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SynapsesSynapses
Types of cell-cell junctionsTypes of cell-cell junctions
Tight junctionsTight junctions membranes fusedmembranes fused
Gap junctionsGap junctions close juxtaposition (2-4 nm)close juxtaposition (2-4 nm) electrical synapseelectrical synapse
Chemical synapsesChemical synapses synaptic cleft (20-30 nm)synaptic cleft (20-30 nm) polarizedpolarized
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Multiple types of synapsesMultiple types of synapses
Vesicle varietiesVesicle varieties
6.4
Spherical agranularvesicles
Reciprocal junction
Spherical granular
Flattened vesicles
6.3
+
-
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Multiple types of synapsesMultiple types of synapses
Multiple patterns of connectivityMultiple patterns of connectivity AxodendriticAxodendritic DendrodendriticDendrodendritic AxoaxonicAxoaxonic AxosomaticAxosomatic etc.etc.
6.1
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Steps in synaptic transmissionSteps in synaptic transmission
SynthesisSynthesis TransportTransport StorageStorage ReleaseRelease InactivationInactivation
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ReleaseRelease
Excitation-secretion couplingExcitation-secretion coupling DepolarizationDepolarization Open voltage-gated CaOpen voltage-gated Ca++++ channels channels CaCa++ ++ influxinflux Bind to CaBind to Ca++ ++ -calmodulin protein kinase-calmodulin protein kinase Phosphorylation of synapsin IPhosphorylation of synapsin I Movement of vesicles to release siteMovement of vesicles to release site ExocytosisExocytosis DiffusionDiffusion
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ExocytosisExocytosis
6.17
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InactivationInactivation
ReuptakeReuptake transporterstransporters
EnzymaticEnzymaticdegradationdegradation metabolismmetabolism excretionexcretion cyclingcycling
DOPAC
DOPA
Tyrosine
ExtracellularDOPAC
Extracellular DA
Monoamineoxidase
HVA
Dopaminetransporter
CytoplasmicDA
ReleasableDA
COMT
3-MT8.13
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Sample questionSample question
In which of the following are the events listed in the correct temporal order (i.e., the temporal order associated with excitation-secretion coupling)?
(a) Depolarization > calcium influx > phosphorylation of synapsin > activation of calcium-calmodulin protein kinase > exocytosis(b) Depolarization > calcium influx > activation of calcium-calmodulin protein kinase > phosphorylation of synapsin > reuptake > exocytosis (c) Exocytosis > phosphorylation of synapsin > calcium influx > activation of calcium-calmodulin protein kinase > depolarization > calcium influx (d) Enzymatic degradation > exocytosis > activation of calcium-calmodulin protein kinase > phosphorylation of synapsin > calcium influx > depolarization(e) Depolarization > calcium influx > activation of calcium-calmodulin protein kinase > phosphorylation of synapsin > exocytosis > enzymatic degradation
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NeurotransmittersNeurotransmitters
Two major types:Two major types:
““Classical”Classical” small water soluble molecules with aminesmall water soluble molecules with amine formed from dietary precursorsformed from dietary precursors
NeuropeptidesNeuropeptides protein synthesisprotein synthesis
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NeurotransmittersNeurotransmitters
PhenylethylaminesPhenylethylamines DA, NE, E, tyramine, etc.DA, NE, E, tyramine, etc.
IndoleaminesIndoleamines 5-HT, tryptamine, melatonin, etc. 5-HT, tryptamine, melatonin, etc.
CholinergicsCholinergics
Amino acidsAmino acids
NeuropeptidesNeuropeptides Enkephalins, substance P, neurotensin, etc.Enkephalins, substance P, neurotensin, etc.
Nonpeptide hormonesNonpeptide hormones
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ReceptorsReceptors
6.5
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ReceptorsReceptors
ClassificationClassification
By LocationBy Location PostsynapticPostsynaptic
DA
GABA
ACH
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ReceptorsReceptors
ClassificationClassification
By LocationBy Location PostsynapticPostsynaptic AutoreceptorsAutoreceptors
DA
GABA
ACH
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AutoreceptorsAutoreceptors
PresynapticPresynaptic SomatodendriticSomatodendritic TerminalTerminal
Release-modulatingRelease-modulating Synthesis-modulatingSynthesis-modulating Impulse-modulatingImpulse-modulating
DA
GABA
ACH
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ReceptorsReceptors
Classification: Classification: By TransductionBy Transduction Mechanism Mechanism
Drug, transmitteror hormone
Receptor
EffectorMembrane
Transduction
Outside cell
Inside cell
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Receptor SuperfamiliesReceptor Superfamilies
1. Ligand-gated channels1. Ligand-gated channels binding site coupled to ion channelbinding site coupled to ion channel transmitter (or drug) gates the channeltransmitter (or drug) gates the channel ionotropicionotropic receptors receptors
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Receptor SuperfamiliesReceptor Superfamilies
1. Ligand-gated channels1. Ligand-gated channels
2. G protein-coupled2. G protein-coupled receptor coupled to G proteinreceptor coupled to G protein G protein activates effectorG protein activates effector metabotropicmetabotropic receptors receptors
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Ligand-gated channelsLigand-gated channelsLigand-gated channelsLigand-gated channels
Ligand opens channelLigand opens channel Ions flow down conc.Ions flow down conc.
gradientgradient RapidRapid RapidlyRapidly
reversiblereversible
5.9
Closed Open
Extracellular side
Cytoplasmic side
Binding
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Ligand-gated channelsLigand-gated channelsLigand-gated channelsLigand-gated channels
Examples:Examples:Nicotinic acetylcholine receptorNicotinic acetylcholine receptor
coupled to sodium channelcoupled to sodium channel drugs: nicotine, curaredrugs: nicotine, curare
GABAGABAAA receptor receptor coupled to chloridecoupled to chloride
channelchannel drugs: sedative-drugs: sedative-
hypnoticshypnotics
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G protein-coupled receptorsG protein-coupled receptors
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G protein-coupled receptorsG protein-coupled receptors
Large family all with Large family all with 7 membrane-7 membrane-spanning regionsspanning regions
Receptor coupled Receptor coupled to G protein, and G to G protein, and G protein stimulates protein stimulates effectoreffector
Slower than Slower than ion-coupledion-coupled
6.22
Receptor
G protein
Precursor
Ionchannel
Secondmessenger
Effectorenzyme
βαγ
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G protein-coupled receptorsG protein-coupled receptors
Two classes:Two classes:
G protein directly coupled to ion channelG protein directly coupled to ion channel effector is ion channeleffector is ion channel
G protein coupled to 2nd messenger systemG protein coupled to 2nd messenger system effector is enzyme that promotes formation effector is enzyme that promotes formation
of intracellular “second messenger”of intracellular “second messenger”
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G protein-coupled receptorsG protein-coupled receptors
Examples:Examples:
CholinergicCholinergicmuscarinicmuscarinic
GABA GABA BB
5-HT5-HT OpioidOpioid DopamineDopamine Norepin-Norepin-
ephrineephrine
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Second messengersSecond messengers
Are many:Are many: CalciumCalcium cGMPcGMP Phosphoinositides Phosphoinositides
(IP(IP33, diacylglycerol), diacylglycerol) cAMPcAMP
cAMP cAMP (cyclic adenosine 3,5-(cyclic adenosine 3,5-monophosphate)monophosphate)
Receptor
G protein
Precursor
Ionchannel
Secondmessenger
Effectorenzyme
βαγ
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cAMPcAMP
Activate protein kinase(phosphorylate protein)
Biologicalresponse
(dephosphorylate byphosphoproteinphosphatase)
Receptor
Gs
ATPcAMP
Adenylylcyclase
6.22
1
2 3
4
5
67
8 9
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Protein phosphorylationProtein phosphorylation
Changes structure/function of proteinChanges structure/function of protein
Consequence depends on function of proteinConsequence depends on function of protein ion channel proteinsion channel proteins enzymesenzymes cytoskeletal proteinscytoskeletal proteins vesicular proteinsvesicular proteins receptorsreceptors gene regulatory proteinsgene regulatory proteins
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Second messengers and protein kinases have many targetsSecond messengers and protein kinases have many targets
from P. Greengard, Science, 2001
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from P. Greengard, Science, 2001
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Gene regulationGene regulation
Second messengers can alter gene regulation:Second messengers can alter gene regulation:
Activate transcription factorsActivate transcription factors Regulate transcriptionRegulate transcription
enhance or supress enhance or supress If enhance - new gene productsIf enhance - new gene products
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Gene regulationGene regulation
Two phases of gene activation:Two phases of gene activation:
Initial phaseInitial phase induction of immediate-early genes (IEGs)induction of immediate-early genes (IEGs)
(e.g., (e.g., cfoscfos, , c-junc-jun, , zif-268zif-268, etc.), etc.) protein products initiate 2nd phaseprotein products initiate 2nd phase
Second phaseSecond phase induction of “late-onset genes”induction of “late-onset genes” products that alter cellular functionproducts that alter cellular function
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Gene regulation by cAMPGene regulation by cAMP
R= regulatory subunitC= catalytic subunit
Transcription factor: CREB (cAMP responseelement binding protein)
CREB stimulates genetranscription (eg., IEGs)
6.34
C C
C C
AC
Plasma membraneAgonist
R R
CREB
CRE
R R
Receptor
G
ATPcAMP
Proteinkinase A
mRNA
P
Nuclearmembrane
Nucleus
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Convergence on CREBConvergence on CREB
6.35
Multiple signallingMultiple signalling
pathways can alter pathways can alter
gene transcriptiongene transcription
via same via same
transcription transcription
factorfactor
2nd messengers
kinases
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SummarySummary
6.37
Drugs of Drugs of abuse are abuse are very effective very effective in inducing in inducing IRGs IRGs
Ca2+ Diacylglycerol IP3 cAMP cGMP
Second messengers
Fourth messengers
Protein kinases
Nuclear membrane
Other genes
CREB-like transcription factors
fos-like Transcription factors
G proteinsCoupling factors
ReceptorsNeurotransmitters
First messengers
Third messengers
6.37
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Home
Saline
Novel
Amphetamine
c-fos mRNA Expression
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Sites of drug actionSites of drug action
1
2 4
56
8
7 3
6.2
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Sample questionSample question
Which of the following classes of drug action would Which of the following classes of drug action would have in common the effect of have in common the effect of increasingincreasing synaptic synaptic transmission?transmission?
(a) facilitation of release; block reuptake; inhibition of synthesis(a) facilitation of release; block reuptake; inhibition of synthesis
(b) blockade of the release modulating autoreceptor; facilitation (b) blockade of the release modulating autoreceptor; facilitation of release; receptor agonistof release; receptor agonist
(c) receptor agonist; receptor antagonist; synthesis inhibition(c) receptor agonist; receptor antagonist; synthesis inhibition
(d) reuptake blocker; facilitation of release; receptor antagonist(d) reuptake blocker; facilitation of release; receptor antagonist
(e) blocks metabolism; block reuptake; inhibits synthesis(e) blocks metabolism; block reuptake; inhibits synthesis