2.3 - Glutamate and Aspartate

neurotransmitter

chemical released at synapse by a neuron that specifically affects postsynaptic cell

hormones

postsynaptic cell released into bloodstream to act on distant targets

Autocoids

acts on tissue from which it was released

neuroactive peptides

short polymers of aa’s; synthesized from genes (ex: endorphins)

small-molecule transmitters

charged molecules, derived from substrates of metabolism regulated at one key enzymatic step

glutamate

- most abundant excitatory aa NT in CNS

- key compound in cellular metabolism

glutamate synthesis (TCA cycle)

oxidative deamination of alpha-ketoglutarate

glutamate breakdown/deanimation (TCA cycle)

via glutamate dehydrogenase → alpha-ketoglutarate

glutamine synthetase

enzyme used for glutamate synthesis in glia cell

glutaminase

enzyme used for glutamate breakdown in neurons

aspartate

excitatory aa NT that is the conjugate base of L-aspartic acid

aspartate synthesis

transamination of oxaloacetate

N-methyl-D-Aspartate (NMDA) and AMPA

mimic glutamate as a NT by binding to a subset of glutamate receptors

reuptake transporters

help glutamate and aspartate cross BBB and membranes

excitatory amino acid transporter (EAAT)

- Unique class of active transport reuptake transporters with five protein subtypes found in neurons and glia.

- Function to remove glutamate or aspartate from the synapse.

- Transport occurs by coupling the influx of the negatively charged amino acid with Na⁺ moving down its electrochemical gradient.

vesicles

highly concentrate small molecule NTs that make ready for quick release in synapse

Vesicular transporter (VGLUT)

- 3 subtypes; 12-transmembrane spanning proteins

- catalyzed uptake of charged NT into vesicles

- ATP-dependent H+ pump creates pH gradient

- swaps 2H+ for charged NT, driving into vesicle against [gradient]

false transmitters

NT analogs + packages the same, but show decreased efficacy

glutamate receptors

Kainate, NMDA, AMPA, Metabotropic

Kainate

- ion channel (Na+ in, K+ out)

- excitatory and desensitizes neurons

- found in spinal cord (pain signal)

NMDA

- ion channel (Ca2+, Na+ in; K+ out)

- complex regulation

- Mg2+ blocks, requires depolarization opening modulated

- acts ac coincidence detectors (activation and recent or not)

NMDA locations

hippocampus, neocortex, etc.

AMPA

- ion channel (Na+ in, K+ out)

- excitatory, and very fast

- learning and memory

Metabotropic Glutamate receptors

- 8 types; linked to Gi or Gq proteins

- inhibitory effects → slower, but long duration

ionotropic glutamate receptors

5 subunit pentamer

Group I Metabotropic (mGluR)

slow excitatory receptors

Group II and III mGluRs

slow inhibitory receptors

mGluRs

7 transmembrane proteins (GPCR)

synaptic plasticity

long-term potentiation changes synaptic strength w/ INCREASE stimulation

long-term potentiation

basis for learning and memory formation; cognition

reuptake

Synaptic activity of glutamate is terminated by ______.

fate of glutamate after uptake

- glial cells → metabolized (via glutamine synthetase)

- presynaptic → recycled back into vesicles

Glutamate roles

brain development, motor control, and pain

brain development (ref. Glu)

regulates growth cones and promotes synaptogenesis (neuron contact)

motor control (ref. Glu)

initiates and sets speed of locomotion

mesencephalic locomotor region (MLR)

- stimulates reticulospinal pathway → ↑ signaling and locomotion

pain

NMDA-R in A-delta and C fibers the basis for fast transmissions of nociception

Epilepsy (ref. Glu)

excess glutamate-mediated excitation and depolarization in foci area correlated to seizures

oxidative stress and excitotoxicity

- excess extracellular Glu increases NMDA signaling = ↑ intracellular Ca2+

- ↑ Ca2+ promotes overactivity = ↑ toxicity (peroxide and free radicals)

Mechanisms of cell death (ref. Epilepsy)

- mitochondria damage from ↑ Ca2+

- promotion of apoptotic transcription factor

NMDA receptor antagonists

reduce neuronal cell death

Ketamine and PCP

- NMDA receptor antagonist

- analgesics, hallucinogens

- disrupt motor control, memory, cognition