Receptors and transduction
mechanisms - I
The Neuron by Levitan & Kaczmarek
– Chapter 11
ligand gated ion channels (LGIC) or
Ionotropic receptors
FAST
DIRECT
Ionotropic receptor subunits
Glutamate
5-hydroxy
GABA Acetylcholine Glycine tryptamine
AMPA NMDA Kainate
(serotonin)
GluR1
GluR2
GluR3
GluR4
NR1
NR2A
NR2B
NR2C
NR2D
tetrameric
GluR5
GluR6
GluR7
KA1
KA2
1-7
1-4
1-4





-3
1-10
1-4



1-4

pentameric
5-HT3
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 (Gproteins) that activate intracellular second messenger pathways
SLOW
INDIRECT
Metabotropic receptors (Gprotein-coupled receptors, GPCR
Glutamate
GABAB
Class1 ClassII ClassIII
mGluR1 mGluR2 mGluR4 GABABR1
mGluR5 mGluR3 mGluR6 GABABR2
mGluR7
mGluR8




Dopamine
D1A
D1B
D2
D3
D4
Acetycholine
(muscarininc)
M1
M2
M3
M4
M5
5-HT
5-HT1
5-HT2
5-HT3
5-HT4
5-HT5
5-HT6
5-HT7
histamine
H1
H2
H3
Ionotropic receptors - Generic structure
Tetrameric or pentameric assembly of receptor subunits
Assembly of either similar (homomeric) or different subunits (heteromeric)
Subunits
Nicotinic acetylcholine receptor
(pentameric)
Ionotropic receptor subunits
Glutamate
5-hydroxy
GABA Acetylcholine Glycine tryptamine
AMPA NMDA Kainate
(serotonin)
GluR1
GluR2
GluR3
GluR4
NR1
NR2A
NR2B
NR2C
NR2D
tetrameric
GluR5
GluR6
GluR7
KA1
KA2
1-7
1-4
1-4





-3
1-10
1-4



1-4

pentameric
5-HT3
A model for iGluR activation and
desensitization
So what are the most important
NT in the mammalian brain?
• glutamate and GABA are the most
abundant which mediate fast transmission
in the CNS via ionotropic receptors
(LGICs)
• In general, GABA is inhibitory whereas
glutamate is excitatory on PS neurons
Effects of glutamate-induced excitotoxicity
Generalised model of
ionotropic glutamate
receptor (iGluR)
The modular nature of iGluR subunits
Madden, D.
THE STRUCTURE AND
FUNCTION OF GLUTAMATE
RECEPTOR ION CHANNELS
(2002). Nature Revs Neurosci. 3,
91.
The N terminus is extracellular
NTD is followed by the S1 half-domain, two transmembrane (TM) domains with an intervening reentrant P loop, the S2 half-domain and a third transmembrane domain.
The C 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, which is homologous to
the bacterial glutamine-binding protein QBP. The structure of this domain is shown as a ribbon diagram.
It consists of two lobes (lobe I, blue; lobe II, red), separated by a ligand-binding cleft.
The 'dimer-of-dimers' model of iGluR assembly
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 right-hand figure). The crystallographically
observed S1S2 dimer probably corresponds to this secondary dimerization interaction.
NMDA receptor
AMPA receptor
Kainate receptors
So why have multiple iR?
• The post-synaptic response to stimulation can
be modulated in the short term (i.e. for hundreds
of milliseconds) or for the long term (hours, days
or even weeks!!).
• Synaptic strength is increased or decreased by
altering the level of post-synaptic depolarisation.
This is achieved through changing how well
receptors respond to stimulation,
– by altering the length of time they are active,
– the number of receptors physically present or
– by altering the amount of L-glutamate that is released
into the the synaptic cleft
GABA receptors
GABA - major inhibitory NT in the mammalian CNS
GABA receptors are pentameric in structure
3 classes
GABAA and GABAC receptors are ionotropic,
GABAB receptors are metabotropic
GABA
Cl-
GABAA receptor binding sites
Benzodiazepine
– allosteric agonist - tranquilisers / anticonvulsants
Barbiturates
– prolong action of GABA - anaesthetics / hypnotics
Imbalances in NT levels
excess
deficit
acetylcholine
Alzheimers?
serotonin
insomnia
depression obesity
bulemia anxiety
bipolar synesthesia
dopamine
GABA
Glutamate
feisty violent
Schizophrenia
novelty seeking
parkinsons
depression
Anxiety
panic attacks,
schizophrenia
Drug
nicotine
atropine
muscarine
prozac
LSD
psilocybin
Ecstasy
amphetamines
MAO inhibitors
cocaine
Chlorpromazine
barbituates valium
Epilepsy
Neuronal death
green agonist (mimic)
blue increases the transmitter (reuptake inhibitors etc.)
red antagonist
orange decreases the transmitter (inhibits release etc.)