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Receptors and transduction mechanisms I – MV Hejmadi
How does the neuron determine which neurotransmitter (NT) to respond to? What should the response be?
Neuronal communication at the synapse is mediated by the specific activation of receptors by NT. Therefore
the nature of the response relies mainly on specific receptors at the post-synaptic membrane. These receptors
must
1) Bind to the NT
2) Transduce a signal into the post-synaptic neuron
Classical neurotransmitters (NT) bind to two classes of receptors, ionotropic and metabotropic resulting in a
change in the excitability of the plasma membrane. These 2 classes of receptors differ in their structural
and pharmacological properties.
Ionotropic receptors (iR): The ionotropic receptors are ligand gated ion channels (LGIC), ie upon binding to
a NT that has been released from presynaptic terminal, charged ions such as Na+ and Ca2+ pass through a
channel in the centre of the receptor complex. This flow of ions results in a depolarisation of the plasma
membrane at the post synaptic terminal and the generation of an electrical current that is propagated down
the processes (dendrites and axons) of the neuron to the next in line. These receptors mediate rapid and
reversible transmission due to the direct coupling of the receptor to the ion channel it gates. (Fig 11-8,
Levitan).
REF: Madden, D. The structure and function of glutamate
receptor ion channels (2002). Nature Revs Neurosci. 3, 91.
A model for iGluR activation and desensitization
Upper row: ionotropic glutamate receptor (iGluR)
channel physiology. In response to the application of
glutamate to mouse embryonic hippocampal neurons,
non-NMDA (N-methyl-D-aspartate) iGluRs open and
then rapidly desensitize to a steady-state level. Middle
row: schematic top view of channels in the resting, open
and desensitized states. Binding of glutamate (Glu)
triggers a conformational change that opens the ion pore
(red lightning bolt). Although agonist remains bound, a
further, most likely interdomain conformational change
allows the channel to close again.
Some examples of ionotropic receptors and subunits
Glutamate
Acetylcholine
GABAA
Glycine
(nicotinic)
AMPA NMDA Kainate
GluR1
GluR2
GluR3
GluR4
NR1
NR2A
NR2B
NR2C
NR2D
GluR5
GluR6
GluR7
KA1
KA2
1-7
1-4
1-4





-3
1-10
1-4



1-4

5-hydroxy
tryptamine
(serotonin)
5-HT3
Glutamate receptors are tetrameric – a ‘dimer of dimers’
GABA, Acetylcholine, Glycine and 5-hydroxy tryptamine (serotonin) receptors are pentameric
Metabotropic receptors (G-protein-coupled receptors, GPCR): These receptors are not directly coupled to
their ion channels and transduce the signal via guanyl nucleotide-binding proteins (G-proteins) that activate
intracellular second messenger pathways (Fig 12-2 Levitan). In contrast to ionotropic receptor action
however, these responses are slower and longer lasting.
Metabotropic receptor subunits (a few examples)
Glutamate
Acetycholine
GABAB
Dopamine
(muscarininc)
Class1 ClassII ClassIII
mGluR1 mGluR2 mGluR4 GABABR1
D1A
M1
mGluR5 mGluR3 mGluR6 GABABR2
D1B
M2
mGluR7
D2
M3
M4
mGluR8
D3

M5
D4



5-HT
5-HT1
5-HT2
5-HT3
5-HT4
5-HT5
5-HT6
5-HT7
histamine
H1
H2
H3
Some metabotropic receptors are dimeric (e.g. mGluR and GABABR)
Receptors to the same ligand can signal through different G-proteins – ClassI mGluR increase IP3 and Ca2+ whereas
ClassII mGluR reduce cAMP
What are the major NT in the mammalian brain?
Quantitatively, simple amino acids glutamate and GABA are the most abundant NT in the mammalian brain
and mediate fast transmission in the CNS via iR. In general, although not always (during development),
GABA is inhibitory whereas glutamate is excitatory on post synaptic neurons.
A) L-Glutamate is the major excitatory neurotransmitter in the mammalian CNS, acting through both
ligand gated ion channels (iGluRs) and metabotropic G-protein coupled receptors(mGluR). Activation of
these receptors is responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity
such as long-term potentiation (LTP) and long-term depression (LTD), which are thought to underlie learning
and memory. They are thus also potential targets for therapies for CNS disorders such as epilepsy and
Alzheimer's disease. Functions: IGluRs glutamate receptors play a vital role in the mediation of excitatory
post synaptic potentials (EPSPs) ie on binding glutamate that has been released from a companion cell,
charged ions such as Na+ and Ca2+ pass through a channel in the centre of the receptor complex. This flow of
ions results in a depolarisation of the plasma membrane and the generation of an electrical current that is
propagated down the processes (dendrites and axons) of the neuron to the next in line.
There are multiple Ionotropic Glutamate Receptors (iGluR)
Structure: iGluRs are tetrameric (i.e. a dimer of dimers)
assemblies, and are subdivided into three groups; AMPA,
NMDA and Kainate receptors, based on their pharmacology.
All ionotropic glutamate receptor subunits share a common
basic structure. Like other ligand gated ion channels, such as
the GABAA receptor, the iGluR is pentameric with each
subunit possessing four hydrophobic regions within the central
portion of the sequence (TMI – IV). However, in contrast to
other receptor subunits, the TMII domain forms a re-entrant loop giving these receptor subunits an
extracellular N-terminus and intracellular C-terminus. In addition, the long loop between TMIII and
TMIV, which is intracellular in other ligand gated ion channel subunits, is exposed to the cell surface, and
forms part of the binding domain with the C-terminal half of the N-terminus. (see fig below)
REF: Madden, D. (2002). Nature Revs Neurosci. 3, 91.
The modular nature of iGluR subunits. The
amino terminus of ionotropic glutamate receptor
(iGluR) subunits is extracellular. An amino-terminal
domain (NTD) is followed by the S1 half-domain,
two transmembrane domains with an intervening reentrant P loop, the S2 half-domain and a third
transmembrane domain. The carboxyl terminus is
located in the cytoplasm, where it can interact with
proteins of the postsynaptic density. The S1 and S2
half-domains form the iGluR ligand-binding domain
The 'dimer-of-dimers' model of iGluR assembly30.
Monomers associate most strongly through
interactions between their amino-terminal domains
(NTDs) (star in middle figure). Dimers undergo a
secondary dimerization, mediated by interactions in
the S2 and/or transmembrane domains (stars in righthand figure). The crystallographically observed S1S2
dimer probably corresponds to this secondary
dimerization interaction.
So why have multiple iR? e.g. glutamate activates both AMPA and NMDA receptors, both of which can be
found together on the same synapse. How is synaptic transmission regulated?
In the case of glutamate, the strength of the stimulus controls the activation of either AMPA or NMDA
receptor. There are essential differences in properties of the two receptors. The ion channel gated by
NMDA is permeable to Na+, K+ and Ca2+, but most of the current is carried by Ca2+. A striking feature of
the NMDA receptor is that the ion channel is blocked by extracellular Mg2+ in a voltage-dependent
manner. A weak stimulus will activate the AMPA receptors only; a stronger stimulus will also activate the
NMDA receptors, causing a greatly increased post-synaptic signal. This property is crucial to the role of
NMDA R in certain types of synaptic plasticity. NMDAR expression is region-specific in the mammalian
brain and is also developmentally regulated.
B) GABA (-butyric acid) is a major CNS inhibitory neurotransmitter in the mammalian CNS
GABA receptors can be divided into three classes A, B & C of
GABA
which GABAA and GABAC receptors are ionotropic, while
ClGABAB receptors are metabotropic
The GABAA receptors are found mainly in neurons, glia and
adrenal medulla cells whereas GABAC receptors are found
mainly in the retina The GABAA receptors are pentameric,
consisting of separate subunits with an 2,2, arrangement
similar to that found for neuronal nicotinic receptors. The
ligand binding site is located at the interface between the  and
 subunits. In addition to endogenous GABA, several different
drugs bind to the GABAAR, which allosterically modulate the binding and
kinetics of the ion channel. The benzodiazepine binding site is located at a
similar level at the interface between the  and  subunits. Each subunit is
comprised of four hydrophobic sequences which span the membrane, with a
large extracellular amino terminus containing the binding site and a carboxyl
terminus located intracellularly. Pharmacology distinguishes the A/C and B
receptors. Fast responses are elicited by A & is mimicked by muscimol and
blocked by bicuculine. B elicits slower responses that are insensitive to
bicuculine and mimicked by baclofen