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Neurotransmitter Receptors
in the Postsynaptic Neuron
F Anne Stephenson, University of London, London, UK
Lynda M Hawkins, National Institute of Health, Bethesda, USA
Introductory article
Article Contents
. Introduction
. Interaction of Neurotransmitters with Specific
Postsynaptic Receptor Proteins
. Specialized Set of Postsynaptic Receptor Proteins for
each Neurotransmitter
The neurotransmitter receptor proteins are integral components in the communication
between adjacent cells of the nervous system, spanning the width of the postsynaptic
membrane and protruding into the synaptic cleft and cell cytoplasm. They mediate the
effects of neurotransmitters between adjacent neurons.
. More than 50 Distinct Neurotransmitter Receptor
Types
Introduction
. Activation of Both Directly Coupled and Metabotropic
Receptors by Acetylcholine and Amino Acid
Neurotransmitters
Communication between adjacent neurons in the central
nervous system occurs at specialized regions of the nerve
cells termed the synapse. It is mediated by the movement of
chemical mediators or neurotransmitters across a small
gap that exists between the nerve cells. When a neuron is
activated, it releases molecules of neurotransmitter from
synaptic vesicles localized in the presynaptic terminal by a
Ca2 1 -dependent exocytotic mechanism. The released
neurotransmitter diffuses across the gap between the
neurons, the synaptic cleft, to the postsynaptic membrane.
There are many different types of neurotransmitters. They
are mostly small hydrophilic molecules such as biogenic
amines, e.g. noradrenaline, dopamine and serotonin (also
known as 5-hydroxytrytophan or 5-HT); amino acids, e.g.
g-aminobutyric acid (GABA), glycine and l-glutamate
and low-molecular weight peptides, e.g. enkephalin,
substance P, neurotensin, etc. Neurotransmitters are
unable to cross or permeate passively through the
hydrophobic neuronal postsynaptic membrane. Instead,
they mediate their effects by the interaction with a receptor
embedded in the postsynaptic membrane, the neurotransmitter receptor. This article describes the properties of this
important class of receptor.
. Rapid Synaptic Transmission via Ion Channel-coupled
Neurotransmitter Receptors
. Biochemical Signalling at Synapses via Metabotropic
Neurotransmitter Receptors
. Activation of Mainly Metabotropic Receptors by Small
Peptides and Biogenic Amine Neurotransmitters
. Signalling and Encoding Abilities of a Synapse Defined
by its Complement of Specific Receptor Proteins
. Summary
binding site on the neurotransmitter receptor and subsequent removal from the synaptic cleft by either an Na 1 dependent transporter protein or by enzymatic inactivation, as occurs for the hydrolysis of acetylcholine by
acetylcholinesterase. This is summarized in Figure 1.
Presynaptic
terminal
Neurotransmitter
transporters
Neurotransmitter
γ
αβ
Interaction of Neurotransmitters with
Specific Postsynaptic Receptor Proteins
Neurotransmitter receptors are integral membrane proteins, i.e. they span the width of the postsynaptic
membrane and protrude both into the synaptic cleft and
into the cell cytoplasm. The interaction of the neurotransmitter with the neurotransmitter receptor is a noncovalent,
reversible interaction resulting in a conformational change
in the receptor protein leading to either an alteration in the
permeability of certain ions through the membrane or the
activation of intracellular enzymes (see below). Neurotransmitter action is terminated by diffusion away from its
Ligand-gated ion
channels
Effector
G protein-coupled
receptors
Postsynaptic neuron
Neurotransmitter receptorassociated proteins
Figure 1 A typical synapse in the central nervous system.
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1
Neurotransmitter Receptors in the Postsynaptic Neuron
Specialized Set of Postsynaptic
Receptor Proteins for each
Neurotransmitter
Initially, it was thought that each neurotransmitter
interacted with a single type of receptor; thus, for example,
the excitatory amino acid neurotransmitter, l-glutamate,
mediates neurotransmission by binding with high affinity
to the l-glutamate receptor. However, the advent of
molecular cloning revolutionized this original concept
and it is now clear that there exists a family of
neurotransmitter receptors for each neurotransmitter.
Thus, l-glutamate is now known to be the endogenous
activator of the family of glutamate receptors. The
different members of a family of neurotransmitter receptors are encoded by separate genes; thus, they are distinct
proteins. However, these different proteins share a high
degree of amino acid sequence similarity. Receptors that
are ion channels are multisubunit proteins; that is, they are
formed by the coassembly or coassociation of the receptor
gene products. Neurotransmitter receptors whose transduction mechanism is intracellular enzyme activation, i.e.
metabotropic or G protein-coupled receptors, are mostly
single-subunit proteins. Ion channel receptors have the
potential for the greatest number of different receptor
subtypes, which is called receptor diversity. This is because,
for a fixed number of receptor genes, there are many
different ways that the gene products can coassemble to
form a functional receptor. For metabotropic receptors,
the number of different receptors within one family is
dependent only on the number of receptor genes.
k1
k –1
R
+
L*
RL*
Free
Bound
kD =
k –1
k1
Figure 2 The principles of radioligand-binding assays. The receptor (R)
preparation and radioligand (L) are incubated to equilibrium. The bound
radioactivity is then separated from the free, most frequently by rapid
filtration. The bound radioactivity thus yields a measure of the receptor
present. Using saturation-binding curves and Scatchard transformation,
the affinity of the radioligand for the receptor can be determined.
to that of the receptor-containing tissue: at equilibrium, the
bound radioactivity, i.e. a measure of the amount of
receptor, can be readily separated from the free ligand by
molecular size fractionation. This may be either filtration
through glass fibre filters or centrifugation. Data generated
by these assays can be transformed using the Scatchard
plot, which permits the determination of the number of
receptors, referred to as Bmax, and the dissociation
constant, Kd, i.e. the strength of the binding between the
radioactive ligand and receptor. Figure 2 shows the
principles of the radioligand-binding assay.
Alternatively, the different receptor families can be
characterized by virtue of their respective transduction
mechanisms using either electrophysiological methodology (ion channel receptors) or by enzyme activation (G
protein-coupled receptors).
More than 50 Distinct Neurotransmitter Rapid Synaptic Transmission via Ion
Channel-coupled Neurotransmitter
Receptor Types
Receptors
There are over 50 different neurotransmitters and each
neurotransmitter binds to its own family of neurotransmitter receptors. Because of this selectivity, neurotransmitter receptors are primary targets for pharmacological
intervention. Drugs that mimic the action of the neurotransmitter are receptor agonists, whereas drugs that bind
to the same site as the neurotransmitter but do not result in
receptor activation are receptor antagonists. Some drugs
can also discriminate between subtypes of the same
receptor family.
Neurotransmitter receptors are detected and characterized by radioligand binding assays. These assays involve
the incubation to equilibrium of a high-affinity, radioactive
ligand with a tissue preparation, usually membranes,
containing the receptor. The radioactive ligand could be
either the natural neurotransmitter or a synthetic agonist
or antagonist specific for the receptor under study.
Generally, this ligand is of low molecular weight compared
2
As mentioned above, neurotransmitter receptors can be
divided into two broad classes based on their transduction
mechanisms following receptor activation. Rapid synaptic
transmission is mediated by neurotransmitter receptors
that are ligand-gated ion channels. The interaction of the
neurotransmitter with the respective neurotransmitter
receptor for a ligand-gated ion channel results, within
milliseconds, in the opening of either a cation- or anionselective integral ion channel. Depending on the selectivity
of the ion channel and the membrane resting potential, this
results in depolarization or hyperpolarization of the
recipient neuron. Prolonged exposure to the neurotransmitter leads to a waning of the conductance changes, i.e.
desensitization. Examples of neurotransmitters that gate
ion channels are, for excitatory responses, acetylcholine,
glutamate, serotonin (5-HT) and adenosine triphosphate
(ATP), and, for inhibitory responses, g-aminobutyric acid
Neurotransmitter Receptors in the Postsynaptic Neuron
(GABA) and glycine. Generally, depolarization results
from the gating of cation channels, whereas hyperpolarization is the result of the opening of anion channels. But
note that GABA can mediate excitatory responses in
neonatal hippocampal neurons but this is probably due to
the unusual resting potentials in these cells. Also, all the
ionotropic glutamate receptors are permeable to Ca 2 1
except those receptors that contain the RNA edited form of
the GluR2 subunit.
Nicotinic acetylcholine, 5-HT3, GABAA, GABAC and
glycine receptors all belong to the same superfamily of
ligand-gated ion channels, of which the best characterized
is the peripheral nicotinic acetylcholine receptor (nAChR),
which is expressed at the neuromuscular junction. All
members of this family share structural features and
significant amino acid sequence homologies, even though
acetylcholine and 5-HT gate cation channels and GABA
and glycine receptors gate anion channels. They are all
pentamers, i.e. they are formed from the coassembly of five
polypeptide chains with molecular weights in the region
40–70 kDa. They have four transmembrane domains in
each polypeptide, TM1–TM4; the TM2 transmembrane
domain forms the inner lining of the channel. A further
common feature is a large N-terminal extracellular
domain, which contains a conserved cys-cys b loop
structure whose function is unknown. The C-terminal
region of the subunits is also located extracellularly.
nAChRs are anchored and clustered in the postsynaptic
membrane by the protein, rapsyn. Different proteins have
similar roles for the other ligand-gated ion channels.
Figure 3a summarizes the pertinent features of the nAChR
ligand-gated ion channel superfamily.
NT
C
α2
C 192
C
C 193
CT
Ι
ΙΙ
ΙΙΙ
β
Out
In
(a)
Acetylcholine
binding sites
γ
ΙV
α1
δ
(c)
Na+
ACh+
K+
NT
–
ΙΙ
ΙΙΙ
ΙV
Out
In
110 Å
Ι
–
CT
80 Å
(b)
(d)
Rapsyn
Figure 3 Pertinent features of ligand-gated ion channel neurotransmitter receptors. (a) The key features, including the transmembrane topology of
nicotinic acetylcholine, g-aminobutyric acid (GABAA), glycine and serotonin (5-HT3) receptors. (b) The key features of the ionotropic glutamate receptors.
NT, N-terminal; CT, C-terminal; I, II, III, IV are the membrane domains; the red arrows point to the sites of N-glycosylation; C-C, the cys-cys loop. (c) The
arrangement of the subunits and the channel pore of the nicotinic acetylcholine receptor as viewed perpendicular to the plane of the membrane. (d) The
nicotinic acetylcholine (ACh) receptor in the membrane together with the acetylcholine-binding site (drawn to scale). (d) Reproduced in part from
Miyasawa A et al. (1999) Nicotinic acetylcholine receptor at 4.6 Å resolution. Journal of Molecular Biology 288: 765–786, by permission of the publisher,
Academic Press.
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Neurotransmitter Receptors in the Postsynaptic Neuron
The quaternary structure of ionotropic glutamate
receptors is uncertain at the present time. However, it is
known that they are heteromeric, with functional receptors
being composed of four or five polypeptide chains. These
subunits are all larger than those found for members of the
original ligand-gated ion channel superfamily, with
molecular weights in the range 120–180 kDa. Each has
four membrane domains but, in contrast to the receptors
described above, only three of these span the membrane.
The second membrane domain is monotropic, i.e. it does
not span the lipid bilayer but it does form the inner lining of
the channel lumen. The C-terminal portion of the subunit
is intracellular. The ionotropic glutamate receptor subunits do not contain the cys-cys b-loop structure, nor do
they share any amino acid sequence similarity with
nAChRs, GABAA/C or glycine receptors.
ATP-gated neurotransmitter receptors are termed P2X
receptors. They are also multisubunit proteins but they are
different to both the nAChR and glutamate receptor
families. There are seven different P2X subunits, which can
assemble as either homomultimers or heteromultimers to
form functional channels. The number of subunits in each
channel molecule is not known. P2X subunits each have
two transmembrane domains that contribute to the
formation of the ion channel; both the N- and the Ctermini of each subunit are located intracellularly. The
properties of ligand-gated ion channels are summarized in
Table 1.
Biochemical Signalling at Synapses via
Metabotropic Neurotransmitter
Receptors
Neurotransmitter receptors that mediate slower responses
at the synapse, of the order of seconds, are metabotropic or
alternatively, G protein-coupled receptors. For this
receptor family, the signalling mechanism consists of a
receptor protein, a guanine nucleotide protein (G protein)
and an effector molecule, which is an enzyme that catalyses
the production of intracellular messengers. Metabotropic
receptors are the largest family of neurotransmitter
receptor. The prototype is the b-adrenergic receptor, which
itself has structural (but not amino acid sequence!)
homology to the protein bacteriorhodopsin, and homology with rhodopsin, the light-harvesting protein expressed
in the eye. Metabotropic neurotransmitter receptors are,
mostly, single subunit receptors. Each receptor has seven
transmembrane-spanning domains, an extracellular Nterminus and an intracellular C-terminus, which for some
receptors is anchored to the cytoplasmic face of the
membrane by palmitoylation (Figure 4). Receptor heterogeneity in this receptor family is created by the existence of
separate genes for a particular neurotransmitter receptor.
Additional diversity is created by the coupling of different
receptor subtypes to different G proteins, hence different
enzyme effectors. For example, b1-, b2-, b3- and b4adrenergic receptors can couple to Gs proteins and activate
adenylate cyclase, thus increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP);
a1A, a1B and a1D-adrenergic receptors mediate their
responses via coupling to Gp/Gq and subsequent activation
of phospholipase C, resulting in an increase in the second
messengers, diacylglycerol and inositol trisphosphate; a2A,
a2B- and a2D-adrenergic receptors are negatively coupled
to adenylate cyclase via Gi/GO.
Although all members of this family of metabotropic
neurotransmitter receptors have the characteristic seven
transmembrane domains, the family can be subdivided on
the basis of amino acid sequence homologies. Group 1
receptors are 300–400 amino acids in length, they have a
small N-terminal extracellular region, generally bind small
ligands, such as adrenaline, noradrenaline, dopamine,
serotonin, opiates and tachykinins, and have the highest
degree of amino acid sequence similarity within the
Table 1 Ligand-gated ion channel neurotransmitter receptors
Neurotransmitter
Receptor type
Channel selectivity
Acetylcholine
Nicotinic (peripheral)
Nicotinic (neuronal)
P2X1–7
NMDA
AMPA
Kainate
GABAA
GABAC
GlyR
5-HT3
Na 1 /K 1 /Ca2 1
Na+/K+/Ca2+
Na 1 /K 1 /Ca2 1
Na 1 /K 1 /Ca2 1
Na+/K+/Ca2+
Na+/K+/Ca2+
Cl 2
Cl 2
Cl 2
Na 1 /K 1 /Ca2 1
Adenosine triphosphate
Glutamate
g-Aminobutyric acid
Glycine
5-Hydroxytrypamine
AMPA, a-amino-3-hydroxy-5-methylisoxazolepropionate; NMDA, N-methyl-d-aspartate.
4
Neurotransmitter Receptors in the Postsynaptic Neuron
NT
Out
In
(a)
CT
NT
VΙΙ VΙ V
transmembrane regions. Group 2 metabotropic receptors
are significantly larger, with 900–1200 amino acids; they
have large N-terminal and C-terminal domains and,
significantly, they do not share amino acid sequence
similarity with group 1 receptors. Metabotropic glutamate
receptors and GABAB receptors belong to this class.
Interestingly, GABAB receptors are known to be heterodimers. Groups 3 and 4 also exist but, generally, they are
not receptors for neurotransmitters but hormones.
Nonpeptide neurotransmitters bind to their respective
receptors in a cavity within the membrane formed by the
seven transmembrane regions. Residues in the extracellular regions have been implicated in the binding of peptide
ligands.
The different types of adrenergic receptor, together with
their transduction mechanisms, are summarized in Table 2.
Table 3 lists additional examples of metabotropic neurotransmitter receptors.
Out
Ι
ΙΙ
ΙΙΙ
ΙV
Neurotransmitter
binding site
In
G protein-binding
site
CT
Figure 4 Pertinent features of G protein-coupled neurotransmitter
receptors. (a) The key features, including the transmembrane topology of
metabotropic G protein-coupled receptors. NT, N-terminal; CT, Cterminal; the solid rectangles are the seven transmembrane domains; the
red arrows point to the sites of N-glycosylation and the zig-zag line
represents the palmitoylation at the C-terminus. (b) The G protein-coupled
receptor as viewed through the plane of the membrane.
Activation of Both Directly Coupled and
Metabotropic Receptors by
Acetylcholine and Amino Acid
Neurotransmitters
The neurotransmitters acetylcholine, GABA, l-glutamate
and 5-HT are unusual, in that they activate both ionotropic
and metabotropic receptors. Thus acetylcholine activates
either nicotinic acetylcholine receptors, which are ion
channels, or muscarinic acetylcholine receptors, which
belong to the G protein-receptor family. Similarly GABAA/C and ionotropic l-glutamate receptors are ion
channels, whereas GABAB and metabotropic l-glutamate
receptors are G protein-coupled receptors. In each case,
there is no structural or amino acid sequence similarity
between the ionotropic and metabotropic receptors
activated by the same neurotransmitter. Further, their
respective pharmacological profiles are different.
Table 2 Adrenergic receptor subtypes: an example of a G protein-coupled
neurotransmitter receptor which has multiple subtypes that couple to a variety
of G proteins, resulting in activation of different intracellular effector
molecules
Adrenergic receptor subtype
G protein
Transduction mechanism
a1A, a1B, a1D
a2A, a2B, a2C
b1 –b4
Gq/11
Gi/o
Gs
"IP3/DAG
#cAMP
"cAMP
IP3, inositol 1,4,5- trisphosphate; DAG, diacylglycerol; cAMP, adenosine 3’,5’-cyclic
monophosphate.
5
Neurotransmitter Receptors in the Postsynaptic Neuron
Table 3 G protein-coupled neurotransmitter receptors demonstrating receptor multiplicity and diversity
with respect to transduction mechanism
Neurotransmitter
Receptor subtype
G protein
Transduction mechanism
Acetylcholine
Muscarinic M1, 3, 5
Muscarinic M2, 4
P2Y
D1, D5
D2
D3, D4
GABAB (GBR1, 2)
mGluR1, 5
mGluR2, 3, 4, 6, 7, 8
5-HT1A, B, D, E, F
5-HT2A, B, C
5-HT4, 5, 6, 7
SST1-5
Gq/11
Gi/o
Gq
Gs
Gi/o
?
Gi/o
Gq/11
Gi/os
Gi/Go
Gq/11
Gs
Gi/o
"IP3/DAG
#cAMP
"IP3/DAG
"cAMP
#cAMP
?
#cAMP
"IP3/DAG
#cAMP
#cAMP
"IP3/DAG
"cAMP
#cAMP
Adenosine triphosphate
Dopamine
g-Aminobutyric acid
Glutamate
5-Hydroxytryptamine
Somatostatin
IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; cAMP, adenosine 3’,5’-cyclic monophosphate.
Activation of Mainly Metabotropic
Receptors by Small Peptides and
Biogenic Amine Neurotransmitters
The mammalian neuromuscular junction is a specialized
synapse as it receives only excitatory input from the
neurotransmitter, acetylcholine, which interacts with a
homogeneous population of receptors, ligand-gated nicotinic acetylcholine receptors. Receptor activation always
results in depolarization of the muscle cell. In the central
nervous system, synapses are more complex. Each synapse
generally receives either an inhibitory or an excitatory
input from a single type of neurotransmitter; hence,
synapses are referred to as GABAergic, where GABA is
the neurotransmitter, glutamatergic for l-glutamate, etc.
Some synaptic terminals may release more than one
neurotransmitter, thus multiple corresponding neuro6
Group ΙΙΙ
m Glu R
4/7/8
Presynaptic
active zone
AMPA
m Glu R1α
δ2 NMDA
AMPA
Perisynaptic
annulus
Cerebellum
Ext
ras
me ynap
mb tic
ran
e
Signalling and Encoding Abilities of a
Synapse Defined by its Complement of
Specific Receptor Proteins
Group II
m Glu R 2/3
ptic
yna e
ras
n
Ext mbra
me
In Tables 1, 2 and 3, it can be seen that, generally,
metabotropic receptors are activated by low-molecular
weight peptides and biogenic amines, whereas the fastacting ionotropic receptors are activated predominantly by
amino acid neurotransmitters, the noted exception being
acetylcholine. Peptides are often coreleased with fastacting neurotransmitters, thus implying a modulatory role
following interaction with the slower-acting G proteincoupled receptors.
Presynaptic
Postsynaptic
specialization
m Glu R 5
Hippocampus
Postsynaptic
Figure 5 Organization of the different types of glutamate receptor at
glutamatergic synapses. The diagram summarizes information that has
accrued from immunochemical studies of hippocampal and cerebellar
glutamatergic synapses, as indicated, using the electron microscope. Up to
four different types of glutamate receptors are found in the postsynaptic
membrane, including both ionotropic and metabotropic receptors. Thus it
can be seen that the signalling and encoding abilities of a synapse must be
defined by the complement of the receptor proteins colocalized at these
synapses. AMPA, a-amino-3-hydroxy-5-methylisoxazoleproprionate;
NMDA, N-methyl-D-aspartate. Reproduced with permission from Takumi Y
et al. (1998) Synaptic arrangement of glutamate receptors. Progress in Brain
Research 116: 105–121, by permission of the publisher, Elsevier Press.
Neurotransmitter Receptors in the Postsynaptic Neuron
transmitter receptors may coexist within the postsynaptic
neuron; however, even at synapses releasing a single
neurotransmitter, the receptors can be heterogeneous with
respect to both the type and subtype of receptor. Thus, the
overall response at the synapse will be a summation or
integration of all the receptor responses. For example, at a
glutamatergic synapse, in the postsynaptic membrane
metabotropic, non-NMDA (N-methyl-d-aspartate) and
NMDA types of glutamate receptors are found. For each
of these, subtypes may coexist. Figure 5 summarizes the
organization of glutamate receptors at a typical glutamatergic synapse.
ionotropic, or they may be metabotropic receptors. This
major class of neurotransmitter receptor is slower in action
because it involves association with the transducer, the
appropriate G protein, followed by intracellular enzyme
activation. Many subtypes of neurotransmitter receptor
may be found at a single synapse in the central nervous
system; thus, the overall response of a synapse will be
defined by its complement of specific receptor proteins.
Other articles describe in more detail the structures and
pharmacological properties of the neurotransmitter receptors, together with more in depth descriptions of their
respective downstream signalling pathways.
Summary
Further Reading
There are many different types of neurotransmitter
molecules which mediate the communication between
adjacent neurons via interaction with integral membrane
proteins, the neurotransmitter receptors. These neurotransmitter receptors can be either fast acting, i.e.
Levitan IB and Kaczmarek LK (1997) The Neuron: Cell and Molecular
Biology, 2nd edn. New York: Oxford University Press.
Stephenson FA and Turner AJ (eds) (1998) Amino Acid Neurotransmission. London: Portland Press.
Zigmond MJ, Bloom FE, Landis SC, Roberts JL and Squire LR (eds)
(1998) Fundamental Neuroscience. London: Academic Press.
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