Topic 10: Glutamate Flashcards
What are amino acid neurotransmitters?
non-essential amino acids: not required in diet, synthesized in most cells of the body
two functional groups: excitatory and inhibitory amino acid NT
What are excitatory amino acid NT?
glutamate, aspartate, cysteate, homocysteate
What are inhibitory amino acid NT?
gamma-aminobutyric acid (GABA), glycine, taurine, alanine
What is aspartate?
released in a calcium-dependent manner
may not be stored in secretory vesicles
may be directly released from cell cytoplasm: not considered a “classic” neurotransmitter
acts at glutamatergic receptors
physiological functions unclear
What is glutamate?
most widely used excitatory neurotransmitter
~90% of all neurons, 80-90% of all synapses are glutamatergic
mediates fast excitatory neurotransmission: sensory, motor coordination, emotion, cognition, memory formation and retrieval
proteinogenic amino acid: abundant throughout cell, concentrated in presynaptic compartments
How is glutamate synthesized?
glutamate synthesis from glutamine
in the CNS the majority of glutamate is recycled from glutamine by the enzyme glutaminase
What are glutamate transporters?
glutamate is abundant throughout the cell
neurotransmitter glutamate is packaged into vesicles to maintain a seperate “pool” of NT
vesicular glutamate transporter (VGLUT) can be used to identify glutamatergic neurons: family of 3 transporters
VGLUTs are structurally and functionally similar to VMAT
Where are VGLUT1 and 2 expressed?
VGLUT1 and 2 are expressed on distinct glutamatergic populations in the CNS
Where is VGLUT3 expressed?
VGLUT3 is expressed in various neurons including GABAergic, cholinergic, and monoaminergic neurons suggesting possible modulatory functions
How is glutamate metabolized?
glutamate is metabolized to glutamine
glutamine synthetase is the enzyme responsible for conversion of glutamate to glutamine
How are EAATs responsible for reuptake of glutamate?
glutamate transporters on the cell membrane are termed excitatory amino acid transporters (EAATs)
non-specific for both glutamate and aspartate
family of 5 transporters (EAAT1-5)
What are the five families of EAATs?
EAAT1 and 2 are expressed on astrocytes
EAAT3 and 4 are expressed on neurons
EAAT5 is expressed in the retina
EAAT expression compartmentalizes glutamate recycling
What are glia in the CNS?
neurons comprise only 50% of the cells in the CNS
the remaining 50% of cells are termed glia
What are the different types of glial cells in the CNS?
astrocytes: define the brain side of the BBB
oligodendrocytes: myelinate axons in white matter
ependymal cells: generate and regulate CSF
microglia: immune surveillance and development
What are the functions of astrocytes?
define the blood brain barrier: regulate intake of nutrients and oxygen
regulate blood flow in the brain
form extensive signaling networks: coupled with electrical synapses, gap junctions
regulate synaptic functions and contribute to plasticity
How are astrocytes involved in cognition?
human astrocytes show dramatic difference from rodent: some consider the ratio of glia to neurons a species marker of intelligence
proposed to contribute to cognitive processes
grafting human astrocytes into moues cortex increases cognitive measures
What are the functional effects of EAATs?
high levels of extracellular glutamate are toxic to neurons
genetic knockdown of EAAT 1 and 2 (astrocytic) result in widespread increases in glutamate levels especially in the striatum
knockdown of activity of EAAT3 (neuronal type) has much more limited effects: astrocyte pathway of glutamate recycling is the dominant pathway
EAAT2 abnormalities are observed in amyotrophic lateral sclerosis (ALS)
How are glutamate synapses an example of tripartite synapses?
glutamatergic synapses are wrapped by astrocyte processes expressing EAAT1/2
glutamate uptake into astrocytes is rapid, high efficiency, and prevents spillover of glutamate into adjacent synapses
astrocytes are the principal site of glutamate breakdown
glutamine is exported from astrocytes and taken up into neurons to be converted back to glutamate
How does MSG cause glutamatergic injury?
MSG can be used experimentally to induce glutamatergic lesions
MSG is proposed as one of the five basic tastes (referred to as umami): acts on glutamate receptors on the tongue
MSG syndrome is a widely reported reaction to MSG
What are the systems that contain glutamatergic neurons?
pyramidal neurons of the cerebral cortex: projections to striatum, thalamus, limbic, brainstem
corticospinal tracts: voluntary motor control
parallel fibers of the cerebellum: excitatory inputs to Purkinje cells
hippocampus
What are glutamate receptors?
glutamate is responsible for fast excitatory synaptic transmission: the most important receptors are ionotropic
synaptic transmission elicits excitatory postsynaptic potentials (EPSP)
huge number of genes involved in GluR expression (16 for ionotropic, 8 for metabotropic)
What are ionotropic glutamate receptors?
AMPA receptors
kainate receptors
NMDA receptors
What are metabotropic glutamate receptors?
group 1: mGluR1, mGluR5, Gq –> PLC Ca2+
group 2: mGluR2, mGluR3, Gi –> decreased cAMP
group 3: mGluR4, mGluR6, mGluR7, mGluR8, Gi –> decreased cAMP
What are AMPA receptors?
named for the specific agonist: synthetic amino acid
non-selective cation channel (passes both Na+ and K+)
four types of subunits (GluR1-4) from heterotetramers (dimers of dimers)
rapid kinetics: onset, offset, desensitization occur within milliseconds, single channel conductance on picosecond timescale (10-12 s)
experimental antagonists: NBQX, CNQX, DNQX
specific mutations in AMPAR (GRIN2A gene) associated with 58% decrease in Parkinson’s risk if also a heavy coffee drinker
