glutamate and GABA Flashcards
glutamate
the main excitatory neurotransmitter in the brain
- present at more synapses than any other neurotransmitter
GABA
main inhibitory neurotransmitter in the brain
synthesis and storage of glutamate
- is synthesized from the conditionally essential amino acid glutamine
- glutaminase turns glutamine into glutamate
- once synthesized, glutamate is packaged into
vesicles by three different proteins:
VGLUT1, VGLUT2 & VGLUT3; - these proteins are called vesicular glutamate transporters (VGLUT)
release & reuptake of glutamate
glutamate is rapidly taken back into the presynaptic cell by a family of five different transporter proteins: excitatory amino acid transporters (EAATs)
- EAAT1-> 5, each with different cellular localizations
- astrocytes (EAAT1,2) take up more glutamate than do
neurons
- major neuronal glutamate transporter is EAAT3;
- EAAT4 are common on Purkinje cells
glutamate receptors-
AMPA
- ionotropic
- fast inward current
Kainate
- ionotropic
- fast inward current
*four subunits make a channel
* subunits dictate agonists/ antagonists
NMDA
- ionotropic
- slow inward current
- opening requires co-agonist and glutamate
- Ca2+ dependent 2nd messengers
- Mg2+ binding site within the ion pore
- coincidence detector
metabotropic receptors
- group I (mGluR1, mGluR5) receptors are located
post-synaptically and mediate excitatory responses by activating phosphoinositide 2nd messenger - group II (mGluR2, mGluR3) and group III (mGluR4, mGluR6, mGluR7, mGlurR8) receptors are located pre-synaptically and signal by inhibiting cyclic adenosine monophosphate (cAMP) formation
long term potentiation (LTP)
- a persistent (>1 hour) increase in synaptic strength
produced by a burst of activity in the presynaptic neuron - initiated by a burst of firing activity (100 stimuli in ~1s)
called tetanus - mediated by activity of NMDA receptors
neurochemistry of LTP
once Ca2+ enters the cell via NMDA receptors, it alters the postsynaptic neuron by:
1. increasing responsiveness of AMPA receptors to glutamate
2. increase the number of AMPA receptors expressed on the post-synaptic membrane
3. triggers the release of retrograde messengers that cause more glutamate to be released from presynaptic neuron
LTP characteristics
- LTP represents cellular model of “coincidence detection” (i.e. memory)
- NMDA antagonists block the induction of LTP, process is mediated by NMDA receptors
- blocking NMDA receptors, particularly in the hippocampus, can interrupt the
formation of spatial memories
glutamate excitotoxicity
- excitotoxicity can occur with overexposure to glutamate
(or other excitatory AA’s), caused by a prolonged depolarization of the postsynaptic neuron
- necrosis: characterized by rapid lysis of the cell due to osmotic swelling
- apoptosis: delayed cascade of biochemical events that leads to DNA breakup and ultimately cell death
synthesis and storage of GABA
GABA is made from glutamate, a reaction that is catalyzed by the enzyme glutamic acid decarboxylase (GAD)
- vitamin B6 derivative pyridoxal phosphate is a cofactor in the synthesis of GABA
- GABA stored in vesicles via vesicular GABA transporters (VGAT)
- VGATs are also capable of transporting glycine into vesicles and are therefore also known as vesicular inhibitory amino acid transporters (VIAAT)
release and inactivation of GABA
- GABA is removed from the synaptic cleft
by three different transporters: GAT-1, GAT-2 & GAT-3 - once recycled, GABA is then
metabolized back to glutamate and succinate by GABA aminotransferase (GABA-T)
GABA- A receptor
- ionotropic
normally post synaptic - contains ion pore specific to Cl-
- made of 5 subunits
- multiple binding sites for multiple ligands
GABA- A receptor activity
Prototypical GABAA receptors are:
- selectively activated by muscimol
- antagonized competitively by bicuculline
- antagonized non competitively by picrotoxin
