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