Psych 181: Dr. AnagnostarasPsych 181: Dr. Anagnostaras

Lecture 5Lecture 5

Synaptic TransmissionSynaptic Transmission

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

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SynapsesSynapses

Know basic terminology:Know basic terminology: SomaSoma AxonAxon DendriteDendrite Synaptic vesiclesSynaptic vesicles Synaptic cleftSynaptic cleft PostsynapticPostsynaptic PresynapticPresynaptic GliaGlia

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2 4

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SynapsesSynapses

Dendrites & Dendrites & spinesspines

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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

Multiple types of synapsesMultiple types of synapses

Vesicle varietiesVesicle varieties

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Spherical agranularvesicles

Reciprocal junction

Spherical granular

Flattened vesicles

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+

-

Multiple types of synapsesMultiple types of synapses

Multiple patterns of connectivityMultiple patterns of connectivity AxodendriticAxodendritic DendrodendriticDendrodendritic AxoaxonicAxoaxonic AxosomaticAxosomatic etc.etc.

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Steps in synaptic transmissionSteps in synaptic transmission

SynthesisSynthesis TransportTransport StorageStorage ReleaseRelease InactivationInactivation

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

ExocytosisExocytosis

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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

Sample questionSample questionIn 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

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

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 acids Amino acids GABA, glutamate, etc.GABA, glutamate, etc.

NeuropeptidesNeuropeptides Enkephalins, substance P, neurotensin, etc.Enkephalins, substance P, neurotensin, etc.

Nonpeptide hormonesNonpeptide hormones

ReceptorsReceptors

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ReceptorsReceptors

ClassificationClassification

By LocationBy Location PostsynapticPostsynaptic

DA

GABA

ACH

ReceptorsReceptors

ClassificationClassification

By LocationBy Location PostsynapticPostsynaptic AutoreceptorsAutoreceptors

DA

GABA

ACH

AutoreceptorsAutoreceptors

PresynapticPresynaptic SomatodendriticSomatodendritic TerminalTerminal

Release-modulatingRelease-modulating Synthesis-modulatingSynthesis-modulating Impulse-modulatingImpulse-modulating

DA

GABA

ACH

ReceptorsReceptors

Classification: Classification:

By TransductionBy Transduction Mechanism Mechanism

Drug, transmitteror hormone

Receptor

EffectorMembrane

Transduction

Outside cell

Inside cell

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

Receptor Superfamilies Receptor 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

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

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Closed Open

Extracellular side

Cytoplasmic side

Binding

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

G protein-coupled receptorsG protein-coupled receptors

G protein-coupled receptorsG protein-coupled receptors

Large family all Large family all with 7 membrane-with 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

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Receptor

G protein

Precursor

Ionchannel

Secondmessenger

Effectorenzyme

βαγ

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”

G protein-coupled receptorsG protein-coupled receptors

Examples:Examples:

CholinergicCholinergicmuscarinicmuscarinic

GABA GABA BB

5-HT5-HT OpioidOpioid DopamineDopamine Norepin-Norepin-

ephrineephrine

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

cAMPcAMP

Activate protein kinase(phosphorylate protein)

Biologicalresponse

(dephosphorylate byphosphoproteinphosphatase)

Receptor

Gs

ATPcAMP

Adenylylcyclase

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2 3

4

5

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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

Second messengers and protein kinases have many targetsSecond messengers and protein kinases have many targets

from P. Greengard, Science, 2001

from P. Greengard, Science, 2001

Gene regulation Gene 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

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

Gene regulation by cAMPGene regulation by cAMP

R= regulatory subunitC= catalytic subunit

Transcription factor: CREB (cAMP responseelement binding protein)

CREB stimulates genetranscription (eg., IEGs)

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C C

C C

AC

Plasma membraneAgonist

R R

CREB

CRE

R R

Receptor

G

ATPcAMP

Proteinkinase A

mRNA

P

Nuclearmembrane

Nucleus

Convergence on CREBConvergence on CREB

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Multiple signallingMultiple signalling

pathways can alter pathways can alter

gene transcriptiongene transcription

via same via same

transcription transcription

factorfactor

2nd messengers

kinases

SummarySummary

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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

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Home

Saline

Novel

Amphetamine

c-fos mRNA Expression

Sites of drug actionSites of drug action

1

2 4

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8

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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