DBM - Chapter 8 - Glutamate and GABA

VGLUT

vesicular glutamate transporters: VGLUT1, VGLUT2, VGLUT3

found only in glutamatergic neurons

glutamate transporters (EAATs)

remove glutamate from the synaptic cleft

found in both neurons and glia

EAAT2

glutamate transporter expressed in glia (astrocytes), accounts for ~90% of glutamate uptake in brain

EAAT2 KO mice:

• shortened life span

• more susceptible to induced seizures

Downregulation in ALS

• enhanced EAAT2 improves motor function + lifespan

EAAT1

glutamate transporter expressed in glial cells in the cerebellum

decreased uptake can contribute to neuronal hyperexcitability, cell death

AMPA receptor

ionotropic glutamate receptor

voltage-gated Na+ channel

NMDA receptor

ionotropic glutamate receptor; major source of excitability

Na+ and Ca2+ channel

both glutamate and glycine or D-serine must bind at the same time

Mg2+ block expelled by depolarization (via AMPA receptors)

• biological coincidence detector

kainate receptor

ionotropic glutamate receptor

Na+ channel

metabotropic glutamate receptors

mGlur2, 3, 4, 6, 7, 8:

• inhibit AC (Gi)

• majority presynaptic (autoreceptors)

mGlur1, 5:

• activate PLC (Gq)

• majority postsynaptic

  • promote LTP or LTD

glutamate and schizophrenia: NMDA receptor hypofunction hypothesis

NMDA receptor antagonists (PCP/ketamine) induce positive, negative, and cognitive symptoms in normal subjects

• exacerbate symptoms in pt with schizophrenia

• PCP and ketamine are psychotomimetics - non-competitive antagonists

NMDA receptor deficit in some pts with schizophrenia

domoic acid

kainic acid (KA) analog, 3x potency

neurotoxic

Long-Term Potentiation (LTP)

cellular basis of learning and memory

influx of Ca2+ ions through NMDA channels activates CamKII

• phosphorylates existing AMPA receptors

• enhances sensitivity to glutamate

• more AMPA receptors inserted into postsynaptic membrane

Fragile X Syndrome

mGLur5 activation promotes LTD

loss of FMRP → loss of inhibition in response to mGluR5, excessive mRNA translation, increased LTD

glutamate excitotoxicity

prolonged depolarization of receptive neurons → eventual damage or death

injection of monosodium glutamate (MSG) damages arcurate nucleus of hypothalamus

damage at postsynaptic sites, not nerve terminals

glutamate excitotoxicity: mechanism

excessive Ca2+ influx → activates molecules capable of degrading essential proteins and cellular membranes

necrosis due to lysis

damage may also occur with brain ischemia, TBI, etc.

• massive release of glutamate in affected area

GABA

synthesized only by GABAergic neurons

• only functions as NT, only in the CNS

made from glutamate, catalyzed by glutamic acid decarboxylase (GAD)

vesicular GABA transporters (VGAT)

move GABA into vesicles

GABA uptake

GABA removed from synaptic cleft by three different membrane transporters

1. GAT-1 (neurons/astrocytes)

2. GAT-2 (neurons/astrocytes)

3. GAT-3 (astrocytes)

GABA aminotransferase (GABA-T)

in GABAergic neurons, GABA metabolized to glutamate and succinate by GABA-T

in astrocytes, metabolized to glutamate by GABA-T

• glutamate converted into glutamine by glutamine synthetase

• glutamine back into GABAergic neurons

GABA_A receptor

ionotropic GABA receptor

allows Cl^- to move from outside to inside

pentamer, considerable heterogeneity in pharmacological properties`

GABA_B receptor

metabotropic GABA receptor

not activated by BDZs or barbituates

require two subunits to function

1. as autoreceptors: inhibit VGCC’s or inhibit cAMP formation

2. as postsynaptic receptors: inhibiting cAMP formation or opening K+ channels

benzodiazepines (BDZs) and barbituates

bind to GABA_A receptors at sites distinct from GABA binding → positive allosteric modulation

• potentiate effects of GABA on the GABA_A receptor

benzodiazepines (BDZs)

increase potency of GABA

cannot open the channel without GABA

only modulatory activity

barbituates

high doses can open channel in absence of GABA → allosteric agonist

lethal

non-BDZ compounds (hypnotics)

dissimilar chemical structure to BDZs

almost entirely the same pharmacodynamics

positive allosteric modulators (PAMs) at BDZ receptor-site on GABA_A receptor

gabapentinoids

used for epilepsy, pain (fibromyalgia), GAD, bipolar

do not bind to GABA receptors or have GABAergic function

inhibit specific function or VGCC’s to mediate pharmacological effects