Receptors and transduction mechanisms - I

The Neuron by Levitan & Kaczmarek

– Chapter 11

ligand gated ion channels (LGIC) or Ionotropic receptors

FAST DIRECT

Ionotropic receptor subunitsGlutamate

AMPA NMDA Kainate GABA Acetylcholine Glycine

5-hydroxy tryptamine (serotonin)

GluR1 NR1 GluR5 1-7 1-10 1-4 5-HT3 GluR2 NR2A GluR6 1-4 1-4 GluR3 NR2B GluR7 1-4 GluR4 NR2C KA1

NR2D KA2 -3

tetrameric pentameric

SLOWINDIRECT

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

Glutamate Class1 ClassII ClassIII

GABAB Dopamine Acetycholine (muscarininc)

5-HT histamine

mGluR1 mGluR2 mGluR4 GABABR1 D1A M1 5-HT1 H1 mGluR5 mGluR3 mGluR6 GABABR2 D1B M2 5-HT2 H2

mGluR7 D2 M3 5-HT3 H3 mGluR8 D3 M4 5-HT4 D4 M5 5-HT5 5-HT6 5-HT7

Metabotropic receptors (G-protein-coupled receptors, GPCR

Ionotropic receptors - Generic structure

Nicotinic acetylcholine receptor (pentameric)Subunits

Tetrameric or pentameric assembly of receptor subunits Assembly of either similar (homomeric) or different subunits (heteromeric)

Ionotropic receptor subunitsGlutamate

AMPA NMDA Kainate GABA Acetylcholine Glycine

5-hydroxy tryptamine (serotonin)

GluR1 NR1 GluR5 1-7 1-10 1-4 5-HT3 GluR2 NR2A GluR6 1-4 1-4 GluR3 NR2B GluR7 1-4 GluR4 NR2C KA1

NR2D KA2 -3

tetrameric pentameric

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

The N terminus is extracellularNTD is followed by the S1 half-domain, two transmembrane (TM) domains with an intervening re-entrant 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.

Madden, D. THE STRUCTURE AND FUNCTION OF GLUTAMATE RECEPTOR ION CHANNELS (2002). Nature Revs Neurosci. 3, 91.

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.

The 'dimer-of-dimers' model of iGluR assembly

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 receptorsGABA - major inhibitory NT in the mammalian CNS GABA receptors are pentameric in structure3 classes GABAA and GABAC receptors are ionotropic, GABAB receptors are metabotropic

Cl-

GABA

Cl-Cl-

GABA

GABAA receptor binding sites

Benzodiazepine – allosteric agonist - tranquilisers / anticonvulsantsBarbiturates – prolong action of GABA - anaesthetics / hypnotics

Imbalances in NT levels

green agonist (mimic) blue increases the transmitter (reuptake inhibitors etc.) red antagonist orange decreases the transmitter (inhibits release etc.)

excess deficit Drug

acetylcholine Alzheimers? nicotine atropine muscarine

serotonin feisty violent insomnia depression obesity bulemia anxiety bipolar synesthesia

prozac LSD psilocybin Ecstasy

dopamine Schizophrenia novelty seeking

parkinsons

amphetamines MAO inhibitors cocaine Chlorpromazine

GABA depression Anxiety panic attacks, schizophrenia

barbituates valium

Glutamate Epilepsy

Neuronal death