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GABA and GABA receptors

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    1

    Presynaptic terminalGlial

    Postsynaptic neuron

    2

    GABA and GABA receptors

    Lecture 1. GABAA receptors

    Lecture 2. GABAB receptors

    Lecture 3. GABA homeostasis

    Lecture 4. Modulation of GABAergic

    synaptic transmission

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    3

    What is GABA?

    Inhibitory neurotransmitter.

    ~1/3 of synaptic transmission in the brain is mediated by

    GABA.

    Neurons that synthesize and release GABA is called

    GABAergic neurons.

    -aminobutyric acid

    4

    GABA receptors

    GABAA receptors

    Ligand-gated ion channels

    Fast synaptic inhibition

    GABAB receptors GTP-binding protein coupled receptors

    Slow synaptic inhibition

    GABAC receptors

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    molecular structures

    location and function

    single channel recording

    pharmacology

    two types of inhibition

    Lecture 1. GABAA receptors

    6

    Benzodiazepines

    Barbiturates

    Neurosteroids

    Anesthetics

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    GABAAR is ligand-gated ion channel

    Cytoplasmic side

    Extracellular side

    ChannelPoreReceptor

    Transmitter

    Gate

    8

    Molecular structure of GABAA receptors

    1-3

    Moss & Smart

    2001

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    subunits are part of GABAA receptor family

    1-3

    Moss & Smart

    2001

    Dendrogram of the deduced amino

    acid sequences of GABAAR subunits.

    from Cherubini and Conti 2001

    structure

    functionpharmacology

    10

    Distribution of GABAAR -subunit

    mRNA in rat brain

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    Multiple subunits: 16, 13, 13, , , , ,13

    Each subunit contains 4 putative

    transmembrane domains, TM2 is believed to

    form the lining of the channel.

    Hetero- or homo-oligomeric proteins.

    Pentamer with ::at a ratio of 2:2:1

    subunit composition determines functionalproperties and pharmacology.

    Molecular structure of GABAA receptors

    12

    Location

    Cl-

    Presynaptic terminal

    Glial

    GABA RA Postsynaptic neuron

    Synaptic cleft

    IPSP

    Cl- and HCO3-

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    Nernst equationCl

    10 mM

    -

    Cl125 mM

    -

    E =ClRT [Cl]o

    zF [Cl]iln

    E =Cl[Cl]o[Cl] i

    log-60

    E =Cl -66 mV

    z = charge of diffusible ion (Cl- = -1)

    R = universal gas constant

    T = absolute temperature

    F = Faraday's Constant

    14

    recordingrecording

    Inhibitoryinterneuron Motor

    neuron

    Currentpassing

    Currentpassing

    AP

    IPSP

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    Reversal potential of IPSP

    -55

    -35

    -74

    -99(mV)

    E -Cl

    Postsynaptic

    potential

    Postsynaptic

    current

    Clflux

    -

    Current clamp Voltage clamp

    16

    IPSP reduces cell excitability

    Membrane

    hyperpolarization

    drive membrane potential

    away from the threshold

    potential.

    Reduction in membrane

    resistance

    reduce the excitatory input.

    This is known as shunting

    inhibition.

    Threshold potential

    Threshold potential

    E -Cl

    E -Cl

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    Single channel recording

    GABA

    Closed Open BoundBoundBound Open Closed

    Open

    Closed

    18

    ligand binding sites on GABAA receptors

    benzodiazepine

    picrotoxin

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    GABAA receptor pharmacology

    Agonists GABA, muscimol

    Antagonists Bicuculline, picrotoxin,

    gabazine

    Modulators Zn2+

    Neurosteroids

    Benzodiazepines

    Anesthetics

    Barbituates

    Alcohol

    101 1000

    100

    0

    Response(%)

    Dose

    50

    100

    0

    Response(%)

    Dose

    50

    100

    0

    Respon

    se(%)

    Dose

    50

    KD

    Maximum Response

    affinity

    affinity

    efficacy

    efficacy

    101 1000100

    101 1000100

    20

    Phasic and tonic inhibitions

    high agonist dose ~1

    mM

    quantal release

    Action potential-

    dependent IPSPs

    Action potential-

    independent mIPSPs

    synaptic receptors

    sensitive to gabazine

    low agonist dose ~1M

    unknown mechanisms

    reverse uptake

    spill over

    extracellular matrix

    channel spontaneous

    open

    extrasynaptic receptors

    insensitive to gabazine

    20 pA

    40 ms

    Bicuculline

    50pA

    1 min

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    GABAAR and disease

    GABAAR is a major target for developingtherapeutics. pain

    epilepsy

    anxiety

    depression

    sleeping disorders

    Mutations in GABAARs are found to be linked to

    epilepsy.

    22

    GABAAR Summary

    GABA-gated anion channels.

    The primary inhibitory receptors in themammalian brain.

    Pre-, post-synaptic and extrasynaptic area,mediating inhibitory postsynaptic potentials

    (IPSPs) and tonic inhibition. Important targets for therapeutic agents.

    Mutations in the genes encoding GABAAreceptor subunit correlate with certain type ofepilepsy.

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    Questions

    24

    Lecture 2. GABAB receptors

    molecular structures

    location and function

    modulation

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    GABABRs are G-protein coupled receptors

    Extracellular side

    Cytoplasmic side

    NH2

    COOH

    ReceptorTransmitter

    PPP

    GTP

    G protein

    P

    Channel

    Gate

    26

    Molecular structure of GABAB receptors

    Heterodimer linked

    by coiled-coil

    domain

    GABAB1a-f

    GABAB2, 35%

    homology withGABAB1

    coupled to Gi/Go

    Marshall, FH et al, 1999

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    Function of GABABRs

    PPP

    GTP

    Ca K2+ +

    GABA RB

    Adenylyl cyclase

    28

    GABABRs - postsynaptic

    GABA RB

    fast IPSP

    slow IPSPE

    E

    Cl-

    K+

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    GABABRs - presynaptic

    GluRs

    EPSP

    Threshold

    GABA RB

    GABA RsA

    IPSP

    GABAergic Glutamatergic

    GABA RB

    30

    GABABR function

    opening K+ channels in the postsynaptic

    membrane.

    closing Ca2+ channels in the presynaptic

    terminal.

    GABAergic: autoreceptor

    glutamatergic: heteroreceptor

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    GABABR pharmacology

    Agonists GABA, (-)baclofen, APPA

    Antagonists

    saclofen, phaclofen, CGP35348, CGP55845A

    Modulators

    CGP7930

    32

    GABABR and disease

    GABABR agonist

    antispasticity

    antinociceptive

    suppression of drug craving

    GABABR antagonist

    suppress absence seizure in animal models

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    GABABR Summary

    G-protein coupled receptors.

    Heterodimer with GABAB1 and GABAB2.

    Mediate slow IPSP via opening K+ channel at

    postsynaptic membrane.

    Decrease synaptic release via inhibit Ca2+

    channels in the presynaptic terminal.

    targets for therapeutic agents.

    34

    Function of GABAARs and GABABRs

    Under several conditions GABAR-mediated response can be excitatory. GABAARs

    EIPSC higher than the threshold (Cl- or HCO3

    -).

    Disinhibition

    GABABRs Presynaptic inhibition on inhibitory neurons

    Activating K+ channel may recruit T-type Ca2+

    channel to induce oscillation in thalamus.

    Disinhibition

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    Reference books

    Principles ofneuroscience

    4th Edition

    Eric R. Kandel

    Jame H. Schwartz

    Thomas M. Jessell

    New York: Elsevier

    From neuron tobrain

    4th Edition

    John G. Nicholls

    Robert Martin

    Bruce G. Wallace

    Paul A. Fuchs

    Sunderland: SinauerAssociates


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