- gaba receptors and glutamate receptors mars2010

7/29/2019 - GABA Receptors and Glutamate Receptors Mars2010

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GABA receptors andGlutamate receptors


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System Type

acetylcholinergic acetylcholine nicotinic receptors

acetylcholine muscarinic receptorsmonoaminergic 1-adrenoceptors

2-adrenoceptors

-adrenoceptors

dopamine receptors

serotonin receptor

aminoacidergic GABA receptors

glutamate ionotropic receptors

glutamate metabotropic receptors

glycine receptors

histamine receptors

peptidergic opioid receptors

other peptide receptors

purinergic adenosine receptors (P1 purinoceptors)P2 purinoceptors

Summary of Types of Receptors


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Amino Acids neurotransmitters GABA

Main inhibitory neurotransmitter in thebrain

Inhibitory effects augmented by alcoholand antianxiety drugs like Diazepam(Valium)

Increases influx of Cl- in postsynapticneuron, hyperpolarising it and thusinhibiting it!


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Amino Acidsneurotransmitters.

GLUTAMATE Widespread in brain where it represents

the major excitatory neurotransmitter

Important in learning and memory

Stroke NT-excessive release producesexcitotoxicity:

neurons literally stimulated to death; mostcommonly caused by ischemia due to stroke

Aids tumor advance when released bygliomas55


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GABA Receptors


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GABAergic Molecular Neurobiology

Lscher, Bernhard. Molecular neurobiology of inhibitory synapses. Seehttp://www.bio.psu.edu/People/Faculty/Luscher/.
http://www.bio.psu.edu/People/Faculty/Luscher/http://www.bio.psu.edu/People/Faculty/Luscher/


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Whereas glutamate is the principal excitatory neurotransmitter,

GABA is the principal inhibitory neurotransmitter in the brain

A typical GABA

presynaptic terminal


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GABA synthesis

Biosynthetic enzyme: GAD65, GAD67

GAD65 more highly enriched in nerve terminals, therefore might be more

important for neurotransmission

GAD requires pyridoxal phosphate as cofactor (might be regulated by

GABA and ATP)


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GABA release, reuptake

Vesicular release is the major mechanism

Uptake is mediated by plasma membrane transporters

GAT-1, GAT-2, GAT-3, BGT-1

GAT1-3 in brain, BGT-1 in kidney but may also be in brain

1 GABA

2 Na+

1 Cl-GAT

out in


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Degradation

GABA aminotransferase

(aka GABA transaminase or

GABA T)

Astrocytes and neurons, mitochondrial


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-ketoglutarate glutamate

Summary of GABA synthesis, release, reuptake, degradation1. GABA is formed by removal of

carboxyl group of glutamate, by

the enzyme GAD

2. GABA is packaged into synaptic

vesicles by VIAAT and releasedby depolarization

3. GABA may be taken up by

nerve terminal by GAT proteins

for repackaging into synaptic

vesicles

4. GABA may be taken up by glial

cells, where it undergoes

reconversion to glutamate

(amine group is transferred to -

ketoglutarate, generating

glutamate and succinicsemialdehyde)

5. Glutamate is transported back

into nerve terminal, where it

serves as precursor for new

GABA synthesis


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GABA Receptors There are two basic subtypes;

GABA-a and GABA-b.

GABA-a

GABA-a is the most prevalent in the mammalianbrain.

The GABA-a receptor is similar to acetylcholinereceptor in that it is related to an ion channel.

It is the chloride ionophore. Binding of GABA to this receptor increases the

permeability to chloride ion which causes ahyperpolarization of the neuron or inhibition.


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GABA-a: Structure The GABA-a receptor has four basic

subunits, 2-alpha and 2 beta peptides

which surround a chloride channel.

There are three basic binding sites onthis complex:

The first is the GABA site.

The second is a benzodiazepine site.The third is in the channel and is

essentially a barbiturate site.


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Pathophysiology of GABA Reduced GABA-activity

in local cell assemblies:

Causes Over-excitability & Epilepsy

In striatal output neurons:

Causes Chorea Huntington

Enhanced GABA-activity

In local cell assemblies, this causes:

reduced excitability

inhibition of learning

Anxiolytic

anesthetic


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Pharmacologyof GABA-a receptors GABA-a binding site agonist:

muscimol

GABA-a binding site antagonist:

bicuculline chloride channel blocker:

picrotoxin

allosteric modulatory sites:

benzodiazepines, barbiturates,manesthetics


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Pharmacologyof GABA-b receptors Subtypes:

Pre and Post synaptic

Pharmacology

GABA binding site agonist:

baclofen

GABA binding site antagonist:

saclofen


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GABA receptors

GABAA GABAC GABAB

ionotropic metabotropic

GABA site benzodiazepine site

Selective agonists musci

mol

Diazepam L-baclofen

--- ---

Selective antagonistsbicuculline (6.0) flumazenil 2-hydorxy-s-(-)-saclofen

picrotoxin

Neuropharmacology


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GABA T orGABA-transporter These are antiepileptics drugs

Na Valproate

Vigabatrine = gamma vinyl GABA


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Glutamate receptors


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Synthesis and degradation ofglutamateglutaminase

glutamine glutamate ?


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Glutamate fast neurotransmission

Synthesis, packaging, reuptake, degradation

(error - should

be EAAT)


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Glutamate Receptor Subtypes NMDA Receptor:

Ligand-gated ion channel

- Kainate/AMPA Receptors:

Ligand-gated ion channels

- Metabotropic glutamate receptors:

G-protein coupled


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Molecular diversity of glutamate

receptors:

3 types, based on sensitivity topharmacological agents: AMPA, kainate, N-

methyl d-aspartate (NMDA)

AMPA: homotetramers or heterotetramers

assembled from Glu R1-4 subunits

NMDA: heterotetramers that contain an NR1

subunit, and a subunit from the NR2 family

Kainate: heterotetramers containing subunits

from the KA1,2 family, and from the GluR5-7family


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Glutamate receptors

Responsible formediatingRapid SynapticExcitation inthe CNS


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NMDA (N-methyl-D-aspartate)Receptors Post-synaptic

ligand-gated ionchannel

Widely distributedthroughout CNS

Fast excitatorytransmission

membran

outside

inside

Na

C a

+glycine

NMDA

Zn

PC PMK801

Mg2+

Na Ca+

m em bran e activation of C adepola rization de pe ndent enz ymes

phosphorylation/dephosphorylationproteolysis

2+

2+

2+

2+

Adapted from The Biochemical Basis of Neuropharmacology Cooper

et al.

SubunitsNR1

NR2A-D


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NMDA receptors


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AMPA/ Kainate receptors(-amino-3-hydroxy-5-methyl-isoxazole)

Ligand-gated ionchannels

Increase Na+ andCa+ conductances

Membrane

depolarization Widely distributed

throughout theCNS

membran

outside

inside

Na

Ca

+

kainate / AMPA

Na Ca+

m embrane activatio n of Cadepola rization de pe ndent enz ymes

phosphorylation/dephosphorylationproteolysis

2+

2+

2+

SubunitsAMPA: GluR1-4

Kainate: GluR5-7, KA1, KA2

Adapted from The Biochemical Basis of Neuropharmacology Cooperet al.


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Metabotropic glutamatereceptors G protein coupled receptors which are

linked to a variety of ion channels and

second messenger systems

Presynaptic receptors modulateneurotransmitter release

Postsynaptic receptors modulate

depolarization and second messengersystems


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Metabotropic glutamatereceptor subtypes Type I: mGluR1, mGluR5

Linked to PI hydrolysis/Ca2+ signaltransduction

Type II: mGluR2, mGluR3 Negatively coupled to adenylyl cyclase

Type III: mGluR4, mGluR6-8

Negatively coupled to adenylyl cyclasebut have different agonist profile frommGluR2 and mGluR3


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Pharmacology of Glutamatereceptors AMPA

agonists: AMPA, glutamate antagonists: (CNQX, NBQX)

Kainate agonists: kainic acid, glutamate antagonist: (CNQX)

NMDA agonists: glutamate, aspartate, NMDA antagonists: Ketamine, Phencyclidine, (Mg++)


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AMPA

agonists: AMPA, glutamate

antagonists: CNQX, NBQX

Kainate

agonists: kainic acid, glutamate

antagonist: CNQX

NMDA

agonists: glutamate, aspartate, NMDA

antagonists: D-APV, D-AP5, MK-801, Ketamine,

Phencyclidine, (Mg++)


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Glycine Receptors


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Glycine Synthesis and degradation

Serine hydroxymethyl-transferase

serine glycine ??

High-affinity glycine uptake by GLYT1 and GLYT2


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Glycine neurotransmission

S f GABA th i l t k d d ti


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GCS: glycine cleavage system

Consists of 4 proteins

T protein

L protein

H protein

P protein

Summary of GABA synthesis, release, reuptake, degradation

1. Glycine is synthesized

from serine by SHMT

2. Glycine is packaged into

synaptic vesicles by

VIAAT (same

transporter as for

GABA)3. Glycine is removed from

synapse by GLYT1

(glial, for clearance from

synapse), and GLYT2

(neuronal, for re-uptakeand packaging).

4. Glycine is cleaved by the

glycine cleavage system


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Glycine Receptors Ligand-gated chloride channel Multiple subunits exist (alpha 1-4)

1-4, subunits - homomers in early development, heteromers in adults

Activation results in chloride influx, membranehyperpolarization and neuronal inhibition

No allosteric regulators used as drugs Competitive antagonist: strychnine

Functions of Glycine receptors Major spinal cord inhibitory transmitter

Retinal, brainstem as well

Human mutations in glyR found in startle disease,hyperekplexia, Jumping Frenchman disease


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strychnine It is a crystalline alkaloid used

as a pesticide for the killing ofbirds and rodents Strychnine acts as a blocker or

antagonist at the inhibitory orstrychnine-sensitive glycine

receptor (GlyR), a ligand-gatedchloride channel in the spinalcord and the brain

Strychnine causes muscularconvulsions and eventuallydeath through asphyxia orsheer exhaustion

The most common source isfrom the seeds of theStrychnos nux vomica tree
http://en.wikipedia.org/wiki/Alkaloidhttp://en.wikipedia.org/wiki/Pesticidehttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Glycine_receptorhttp://en.wikipedia.org/wiki/Glycine_receptorhttp://en.wikipedia.org/wiki/Ligandhttp://en.wikipedia.org/wiki/Chloridehttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Convulsionhttp://en.wikipedia.org/wiki/Asphyxiahttp://en.wikipedia.org/wiki/Strychnine_treehttp://en.wikipedia.org/wiki/Strychnine_treehttp://en.wikipedia.org/wiki/Asphyxiahttp://en.wikipedia.org/wiki/Convulsionhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Spinal_cordhttp://en.wikipedia.org/wiki/Chloridehttp://en.wikipedia.org/wiki/Ligandhttp://en.wikipedia.org/wiki/Glycine_receptorhttp://en.wikipedia.org/wiki/Glycine_receptorhttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Pesticidehttp://en.wikipedia.org/wiki/Alkaloid

- gaba receptors and glutamate receptors mars2010

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