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Chapter 8: Glutamate and GABA - Coggle Diagram
Chapter 8: Glutamate and GABA
Glutamate
Glutamate Synthesis, Release, Inactivation
Synthesis
glutamine + H2O + ATP is acted on by glutaminase
glutamate
Packaging/Release/Inactivation
Packaging: 3 vesicular glutamate transporters
VGLUT1
VGLUT2
VGLUT3
VGLUTs: found ONLY in glutamatergic neurons (specific marker)
Release/Inactivation: glutamate removed from synaptic cleft by glutamate transporters by glutamate transporters (EAATs)
EAATs 1-5 (excitatory amino acid transporters) are located in both neurons and astrocytes
EAAT 1 and 2 are expressed in glial cells (on adjacent astrocyte)
EAAT 1 is highly expressed in glial cells in cerebellum
mutant EAAT1: decreased expression and REDUCED capacity for glutamate UPTAKE --> hyperexcitability and cell death
Ex. Mouse Model of ALS: SOD1
excess glutamate causes damage to MOTOR neurons
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Metabotropic partnership (relationship with glutamatergic neurons and neighboring astrocyte): important for maintaining normal levels
Reuptake of glutamate in astrocyte
Glutamate BROKEN DOWN within astrocyte --> glutamine (via glutamine synthetase)
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glutamate: ionized form of glutamic acid (amino acid)
ALL neurons and glial cells contain HIGH amounts of glutamate (use glutamate as protein building block)
Glutamatergic neurons use glutamate as NT AND have even greater concentrations of it
glutamatergic neurons SEPARATE glutamate used for transmission from glutamates used for other functions
Organization and Function of the Glutamatergic System
Receptros: ionotropic and metabotropic
Ionotropic (each has 4 subunits)
AMPA - permeable to Na+
KAINATE - Na+
NMDA - Na+, Ca++
to open channel
BOTH glutamate AND glycine or D-serine (co-agonists) must bind at the SAME TIME
serine racemase - only found in astrocytes
V-dependent Mg++ block: block is REMOVED when membrane is DEPOLARIZED (by adjacent AMPA receptors)
Glutamate and Schizophrenia (NMDA receptor HYPOFUNCTION - REDUCED NMDA receptor function)
NMDA receptor antagonists (PCP, ketamine) --> positive and negative schizophrenia symptoms
PCP and ketamine are psychomimetics - mimic state of psychosis
NMDA receptor deficit in some schizophrenics
Metabotropic receptors: mGluR1 to mGluR8
mGluR2, 3, 4, 6, 7, 8
inhibit AC (Gi)
majority presynaptic autoreceptors
mGluR1 and 5
activate PLC (Gq)
majority postsynaptic
can promote long-term potentiation OR long-term depression (depends on cell type)
Glutamate Receptors in Learning and Memory
mGluR5 activation promotes LTD
Mouse model of Fragile X Syndrome (Fragile X Syndrome caused by FMR1 gene mutations)
treat FMR1 KO mice with CTEP (mGluR5 antagonist)
control: WT mouse show greater latency to enter dark (where foot shock is) than KO mice
because KO mice have reduction in learning/memory because of mGluR5 activation
CTEP treated mice: KO mice have increased latency to enter dark compared with the control KO mice
AMPA and NMDA receptors in cognition
LTP: cellular basis of learning and memory
glutamate released from presynaptic terminal, binds to AMPA and NMDA
Mg++ block removed
Ca++ influx through NMDA, activates CaMKII
phosphorylates existing AMPA receptors
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Mouse
Morris Water Maze: CamKII KO mice - deficit LTP
Doogie mouse (super smart mouse)
overexpresses the NR2B subunit of the NMDA receptor
enhanced LTP and improved learning and memory
more sensitive to chronic pain
Ampakines: AMPA mediated enhancement of cognition
enhance action of AMPA receptors by REDUCING RATE OF DESENSITIZATION
do not activate the receptor itself - "positive allosteric modulators"
enhances dendritic growth of CA1 neurons in hippocampus
Glutamate Excitotoxicity: prolonged depolarization of receptor neurons --> damage/death
injection of monosodium glutamate damages arcuate nucleus of the hypothalamus
damage is at postsynaptic sites (NOT nerve terminals)
Because of Ca++ influx
Ca++ influx activates various molecules that can DEGRADE essential proteins and cellular membranes
Excitotoxic brain damage may also occur with brain ischemia (stroke), traumatic brain injury, etc.
massive release of glutamate occurs in the affected area
treat with NMDA receptor antagonists
Memantine (Namenda): NMDA receptor antagonists that prevents glutamate excitotoxicity
GABA
GABA Synthesis, Release, Inactivation
Synthesis
Glutamate is acted on by glutamic acid decarboxylase (GAD)
GABA
Packaging/Release
moves into vesicles via vesicular GABA transporters (VGAT)
Inactivation
removed from synaptic cleft by 3 different membrane transporters
GAT-1 (neurons and astrocytes)
GAT-2 (neurons and astrocytes)
GAT-3 (astrocytes)
Metabolism
In GABAergic neurons: metabolized to glutamate and succinate by GABA aminotransferase (GABA-T)
In astrocytes: metabolized to glutamate by GABA-T
glutamate converted to glutamine by glutamine synthetase
glutamine back into GABAergic neurons
converted to glutamate, then GABA by GAD
GABA synthesized only by GABAergic neuron (only functions as a neuron), only found in CNS
Organization and Function of the GABAergic system
Receptors: GABAA and GABAB
GABAA (ionotropic): permeable to Cl-
each receptor consists of 5 subunits, 19 different subunits --> heterogeneity in pharmacological properties
Benzodiazepines and Barbiturates
bind to GABAA receptors at sites DISTINCT from GABA binding site (positive allosteric modulation)
potentiate effects of GABA on the GABAA receptor
BDZs
increases potency of GABA
CANNOT open channel without GABA (only modulatory activity)
Barbs
very high doses can open channel WITHOUT GABA (allosteric agonist)
Non-BDZ compounds (hypnotics)
dissimilar chemical structures to BDZs
pharmacodynamics: almost entirely the same as BDZs
similar benefits, side effects, and risks
partial allosteric modulators: bind to BDZ receptor site on GABAA receptor channel
Gabapentinoids: GABA analogs (looks like GABA CHEMICALLY)
do not bind to GABA receptors or have any GABAergic like function
inhibit a specific subunit of VGCCs to mediate their pharmacological effects
GABAB (metabotropic)
require TWO DIFFERENT SUBUNITS to assemble in the membrane to work properly
As autoreceptors: inhibit VGCCs
as postsynaptic receptors: inhibit cAMP formation or open K+ channels