Unit 2 Class 5: Glutamate

glutamate synthesis

glutamine - glutaminase → glutamate (requires energy from atp)

glutamate role

most abundant excitatory amino acid neurotransmitter in the body (found in over 90% of synapses)

→has many different metabolic roles, not just used as NT

what makes something a glutamatergic neuron

what separates true glutamatergic neurons from other neurons containing glutamate:

• contain glutamate specifically as a neurotransmitter and have higher concentrations of glutamate within the cell

• also when they contain VGLU1or VGLUT2 since these are only found in glutamatergic neurons

what is used to transport glutamate into synaptic vesicles

VGLUT1, VGLUT2, and VGLUT3

→ VGLUT1 and VGLUT2 are found only in glutamatergic neurons and thus make good markers

gliotransmission

astrocytes also release glutamate and take up excess glutamate

→ astrocytes act as an intermediary between the pre and post synaptic cell since glutamate needs to be heavily regulated

what protein facilitates glutamate and aspartate reuptake

EAAT1-EAAT5 (excitatory amino acid transporters)

→ these also exist on astrocytes and glial cells for further regulation

→ mice with EAAT2 knocked out make good models for epilepsy.

metabolic relationship between astrocytes and neurons (what enzyme is involved in the breakdown of glutamate)

glutamate is broken down in astrocytes by the enzyme glutamine synthetase into glutamine. Glutamine transporters then bring the glutamine into the cell where it can be resynthesized by glutaminase

ionotropic glutamate receptors (3)

AMPA, NMDA, kainate, each named after their initial agonist

→ when excited, all allow Na+ through, NMDA allows Ca2+ in as well to initiate second messenger cascade

ionotropic glutamate receptors how many subunits

4 (receptor subtypes are made up of different combinations of subunits)

which subunits make up AMPA

GluR 1-4 OR GluA 1-4

which subunits make up kainate

GluR 5-7 and KA1-KA2

which subunits make up NMDA

NR1 and NR2A-NR2D

OR

GluN1 and GluN2A-GluN2D

unique characteristics of NMDA

1. activation allows the flow of both Na+ and Ca2+

2. to open the channel, both glutamate and co-agonist glycine or D-serine must be bound (the co-agonist site is bound to under most conditions)

3. at rest, the receptor is blocked by an Mg2+ ion that only dissociates when the membrane is strongly depolarized

relationship between NMDA receptor and abused drugs

there are many secondary binding sites on NMDA for abused drugs like PCP and ketamine which block the channel

→ this makes them non-competitive antagonists

metabatropic glutamate receptors and their three groups

eight total, designated mGluR1-mGluR8

• group 1: mGluR1 and mGluR5 (excitatory, attached to Gq protein)

• group 2: mGluR2 and mGluR3 (inhibitory autoreceptors attached to Gi/o protein)

• group 3: mGluR4, mGluR6, mGluR7, mGluR8 (inhibitory, Gi/o)

long term potentiation (what does it require)

the strengthening of a synapse following a strong stimulation

requires:

1. release of glutamate from a nerve terminal

2. strong activation of NMDA in the post synaptic cell (Ca2+ MUST enter the cell after tetanus, making NMDA critical receptor)

in LTP what happens when Mg2+ is dissociated and Ca2+ enters the cell

several protein kinases are activated (CAMKII) and this causes more AMPA receptors to insert themselves into post synaptic membrane (up regulation)

early LTP and 2 stages/what they are measured by

early LTP lasts a few hours

1. induction phase: occurs during/immediately after strong presynaptic input (the actual learning event, NMDA receptors are necessary for this)

2. expression phase: represents enhanced synaptic strength (measured by AMPA up regulation)

late LTP

lasts days, months, years

result of Ca2+ (second messenger) induced protein synthesis involving CREB and BDNF production

→ facilitates dendritic growth/new connections, part of the retrograde message to upregulate AMPA and encourage exocytosis in the presynaptic cell)

PKM Zeta

facilitates the maintenance of LTP

→ produced following the second messenger effect of Ca2+, immobilizes the AMPA receptors preventing them from being removed from the membrane