lecture 5 - Neurotransmitter receptor signalling Flashcards
neurotransmitter
a chemical substance which is released at the end
of a nerve fibre by the arrival of a
nerve impulse and, by diffusing across
the synapse or junction, effects the transfer of the
impulse to another nerve fibre, a muscle fibre, or
some other structure
Glutamate
Accounts for >90% of synaptic connections in the human brain
Many papers start “Glutamate is the major excitatory neurotransmitter in
the vertebrate nervous system….”
Key fast neurotransmitters in the CNS
Ionotropic Glutamate receptors
AMPA Receptor Subunit Topology
- consists of 4 subunits
- on m2 - core of the receptor - has a qr binding site- -single a.a transportation from a glmatine to —- - amplifies the receptors not permeable to calcium
Glutamatergic synaptic transmission -
fast
Properties of AMPA Receptors
- Mediate majority of fast excitatory synaptic transmission (mainly postsynaptic localization) –
AMPARs non-selective cation channels permeable to Na+ (goes in) and K+ (goes out) and in some
cases Ca2+ (see below) - Like all ionotropic glutamate receptors comprised of four subunits to form a tetrameric receptor.
- Four different AMPA receptor subunits in mammals GluA1, GluA2, GluA3 and GluA4 these “mix and
match” to produce subtly different receptors. - AMPA receptors containing GluA2 subunit have very low Ca2+ permeability
- Thus activation of all AMPA receptors leads to an influx of Na+ but these receptors are only
permeable to Ca2+ only in the absence of any GluA2(R) subunits (and most AMPA receptors have
GluA2(R)).
Kainate Receptor Subunit Topology
Structure of NMDA receptors
- Cation channel (Na2+ and Ca2+ entry). Channel
opening → depolarization - Activation requires binding of glutamate
(orthosteric site) and a co-agonist (modulatory site)
e.g. glycine or D-serine. - Has a voltage sensitive Mg2+ block which is present
at physiologic concentrations of Mg2+ but
disappears when the cell is depolarized
Mg2+ block of NMDA receptors is voltage-
dependent
- In order for Mg2+ block
of NMDAR to occur the
channel must be open i.e.
glycine and glutamate
must be bound to their
binding sites on the
NMDA receptor. - As membrane potential
is depolarized the Mg2+
block of the NMDA
receptor channel is
progressively removed.
The NMDA receptor is a coincidence
detector
AMPARs often present at same synapse
as NMDARs. Activation of AMPARs
depolarises the membrane sufficiently to
remove Mg2+ block of NMDARs.
* Thus Ca2+ entry through NMDARs is
dependent on pre- and post-synaptic
elements being active at the same time
i.e. the NMDAR is a coincidence detector.
Metabotropic glutamate receptors
Structure of mGlu Receptors
Properties of Metabotropic Glutamate Receptors
Depending on subtype can be pre- and/or postsynaptically localised.
Generally play a modulatory role in synaptic transmission.
Postsynaptic group I mGlu receptors mediate slow depolarization (EPSP)
Presynaptic group II and III mGlu receptors decrease neurotransmitter release.
Involved in the modulation of signalling through K+ and Ca2+
– control excitability of
neurones.
Metabotropic glutamate receptors were desirable targets for drug discovery.
GABA
GABAA receptor structure
- Anion channel (Cl- entry). Channel opening →
hyperpolarization - Made up of 5 subunits [combination of a,b,y,s
and p; most common structure being
(a1)2(b2)2(y2)] - Different isomers have different sensitivity to
alcohol - Found synaptically (short term/phasic inhibition)
and extrasynaptically (modulating the tone of
neural circuits i.e. tonic inhibition, more difficult
to fire action potentials) - Sedative/hypnotic drugs enhance GABAA
receptor activity via the modulatory site
GABAergic synaptic transmission
- fast
GABAA receptor modulators
GABAB Receptors
*Dimer made up of two seven-
transmembrane domain subunits
held together by a coil/coil
interaction between their C-terminal
tails.
*Activation occurs when GABA binds
to the extracellular domain of the B1
subunit
*Located pre- and postsynaptically.
*G protein–coupled receptors that
couple through Gi/Go
Co-activation of GABAA and GABAB
produces long-lasting biphasic IPSPs
Synchronous release of GABA
results in the simultaneous
activation of both GABAA and
GABAB receptors
→ Classical biphasic IPSP
Alcohol impacts neural function in many ways
Full spectrum of alcohol’s pharmacological action remains unclear. This lecture is not exhaustive but will focus on some of the effects on the receptor systems already covered: Glutamate and GABA.
Alcohol (ethanol) can modulate
glutamatergic neurotransmission
*Non-competitive Antagonist (negative allosteric modulator) : NMDA
and AMPA receptors (ionotropic glutamate receptors)
*Reduced glutamate release from pre-synaptic terminal: Increases
activity of mGluR2/3 (group 2 metabotropic glutamate receptor)
Ethanol inhibits NMDA mediated currents
Ethanol dose dependently reversibly
inhibits NMDA-induced inward currents in
cultured neurons (voltage clamp).
* Other studies indicate that ethanol is a
non-competitive antagonist (negative
allosteric modulator)
* Different glutamate receptor subunits
have different ethanol sensitivity which
may explain why different brain regions
are impacted differently by alcohol.
Alcohol acutely
inhibits glutamate
neurotransmission
Chronic alcohol intake leads to compensatory
adaptations in glutamatergic neurotransmission
Behavioural effects of alcohol mediated by
changes in GABAergic signalling
