Neurotransmitters
Reviewed
SMALL MOLECULE NTs:
excitatory AAs = glutamate + aspartate
GLUTAMATE:
pathways
everywhere essentially
roles
major excitatory NT - 40% neurones CNS, 90% have receptors
plasticity/learning
neuron features
identify with immunocytochemistry (cell staining) for VGLUT1/2/3 (not
glutaminase as this is also found in GABAergic)
synthesis
can’t cross BBB so must be made in brain: from glucose via TCA > a
ketoglutarate > glutamate OR from astrocyte shuttle
storage
uptaken into vesicles in neurones via VGLUT1/2/3: Km 1mM (= conc in
cytoplasmic), highly selective for glu over asp, driven by H+ electrochemical
gradient
conc ~20mM in each vesicle
release
AP freq: <400Hz in RGCs up to ~1000Hz in auditory
volume of synaptic cleft = 2x10^-18L
Neurotransmitters 1
, both normal and non vesicular release eg. Xc- is a low affinity antiporter that
transports glu out for cysteine in (enables glutathione production)
ionotropic receptors (fast excitatory)
all tetramers - each subunit 3TM domains with long N term out
non selective cation channels > depolarisation + Ca activation of 2nd
messengers etc
AMPA/NMDA generally colocalised at functional synapses, kainate widely
expressed (but only found at a few central postsynaptic neurones)
receptors named by ability of exogenous drugs to activate:
1. NMDA (n-methyl-d-aspartate)
agonists = glutamate (high 5nM affinity), NMDA
antagonists = D-AP5/V, MK801, ketamine, phencyclidine, memantine
genes = heterotetramer of 2x GluN1 subunits (found everywhere, binds
glycine) + 2x GluN2 (A/B/C/D isoforms - varying distribution, binds glutamate)
(+ GluN3A/B?): activation of BOTH binding sites needed, differing subunits
(expression regulated by neuregulin) determine cation permeabilities
current = channel is voltage sensitive so blocked by extracellular Mg2+ when
Vm is below -50mV - need repetitive depolarising inputs (from AMPA/synaptic
activation) to summate in order to release block to activate = slow onset but
high affinity so stays bound/open longer + slow decay ~50ms (allowing
summation of non synchronous input)
associated with synaptic plasticity
2. AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)
ag = glutamate (200nm affinity), AMPA
antag = CNQX
genes = GluA1/2/3/4 - 2 subunits of one type and two of another, less Ca
permeable and GluA2 NOT Ca permeable
current = faster opening (0.2-0.6ms) and faster decay (desensitised in 10ms)
from lower affinity
Neurotransmitters 2
, 3. kainate
ag = glutamate (500uM affinity), kainate (seaweed)
antag = CNQX, LY294486
genes = GluK1/2/3/4/5 - 1-3 can be alone/homo but 4/5 need to combine with
1-3, low Ca permeability
current = slowest, long lasting depolarisation (from auxillary subunit neto1?)
pre and post synaptic, roles in LTP, presyn modulation of GABA/Glu release
(via G proteins) - both facilitates and inhibits glu activity
metabotropic receptors (slow inhibitory)
GPCRs, mGluR1-8
group I = 1 (hippocampus, cerebellum) and 5 (olfactory bulb, cortex) =
postsynaptic, Gq, opens VGKC > may hyperpolarise or depolarise depending
on location
group II (2/3) and group III (4,6,7,8) = presynaptic - Gi/o, inhibits VGCC >
reduce NT release (glu or autoreceptors to GABA)
reuptake
transporters (+some diffusion) removes glu from synapse in 1ms - 15000-
20000 EAATs/synapse (90% found in astrocytes) with low uM Km so highly
active
EAAT1 (glial cerebellum), 2 (glia, some forebrain neurones), 3 (also GABA) and
4 (neurones), 5 (retinal muller cells)
degradation
Neurotransmitters 3
Reviewed
SMALL MOLECULE NTs:
excitatory AAs = glutamate + aspartate
GLUTAMATE:
pathways
everywhere essentially
roles
major excitatory NT - 40% neurones CNS, 90% have receptors
plasticity/learning
neuron features
identify with immunocytochemistry (cell staining) for VGLUT1/2/3 (not
glutaminase as this is also found in GABAergic)
synthesis
can’t cross BBB so must be made in brain: from glucose via TCA > a
ketoglutarate > glutamate OR from astrocyte shuttle
storage
uptaken into vesicles in neurones via VGLUT1/2/3: Km 1mM (= conc in
cytoplasmic), highly selective for glu over asp, driven by H+ electrochemical
gradient
conc ~20mM in each vesicle
release
AP freq: <400Hz in RGCs up to ~1000Hz in auditory
volume of synaptic cleft = 2x10^-18L
Neurotransmitters 1
, both normal and non vesicular release eg. Xc- is a low affinity antiporter that
transports glu out for cysteine in (enables glutathione production)
ionotropic receptors (fast excitatory)
all tetramers - each subunit 3TM domains with long N term out
non selective cation channels > depolarisation + Ca activation of 2nd
messengers etc
AMPA/NMDA generally colocalised at functional synapses, kainate widely
expressed (but only found at a few central postsynaptic neurones)
receptors named by ability of exogenous drugs to activate:
1. NMDA (n-methyl-d-aspartate)
agonists = glutamate (high 5nM affinity), NMDA
antagonists = D-AP5/V, MK801, ketamine, phencyclidine, memantine
genes = heterotetramer of 2x GluN1 subunits (found everywhere, binds
glycine) + 2x GluN2 (A/B/C/D isoforms - varying distribution, binds glutamate)
(+ GluN3A/B?): activation of BOTH binding sites needed, differing subunits
(expression regulated by neuregulin) determine cation permeabilities
current = channel is voltage sensitive so blocked by extracellular Mg2+ when
Vm is below -50mV - need repetitive depolarising inputs (from AMPA/synaptic
activation) to summate in order to release block to activate = slow onset but
high affinity so stays bound/open longer + slow decay ~50ms (allowing
summation of non synchronous input)
associated with synaptic plasticity
2. AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)
ag = glutamate (200nm affinity), AMPA
antag = CNQX
genes = GluA1/2/3/4 - 2 subunits of one type and two of another, less Ca
permeable and GluA2 NOT Ca permeable
current = faster opening (0.2-0.6ms) and faster decay (desensitised in 10ms)
from lower affinity
Neurotransmitters 2
, 3. kainate
ag = glutamate (500uM affinity), kainate (seaweed)
antag = CNQX, LY294486
genes = GluK1/2/3/4/5 - 1-3 can be alone/homo but 4/5 need to combine with
1-3, low Ca permeability
current = slowest, long lasting depolarisation (from auxillary subunit neto1?)
pre and post synaptic, roles in LTP, presyn modulation of GABA/Glu release
(via G proteins) - both facilitates and inhibits glu activity
metabotropic receptors (slow inhibitory)
GPCRs, mGluR1-8
group I = 1 (hippocampus, cerebellum) and 5 (olfactory bulb, cortex) =
postsynaptic, Gq, opens VGKC > may hyperpolarise or depolarise depending
on location
group II (2/3) and group III (4,6,7,8) = presynaptic - Gi/o, inhibits VGCC >
reduce NT release (glu or autoreceptors to GABA)
reuptake
transporters (+some diffusion) removes glu from synapse in 1ms - 15000-
20000 EAATs/synapse (90% found in astrocytes) with low uM Km so highly
active
EAAT1 (glial cerebellum), 2 (glia, some forebrain neurones), 3 (also GABA) and
4 (neurones), 5 (retinal muller cells)
degradation
Neurotransmitters 3
