Receptors and transduction mechanisms - I

1. Receptors and transduction mechanisms - I The Neuron by Levitan & Kaczmarek – Chapter 11

4. ligand gated ion channels (LGIC) or Ionotropic receptors FAST DIRECT

5. Ionotropic receptor subunits tetrameric pentameric

6. 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 SLOW INDIRECT

7. Metabotropic receptors (G-protein-coupled receptors, GPCR

8. Ionotropic receptors - Generic structure Tetrameric or pentameric assembly of receptor subunits Assembly of either similar (homomeric) or different subunits (heteromeric) Nicotinic acetylcholine receptor (pentameric) Subunits

9. Ionotropic receptor subunits tetrameric pentameric

10. A model for iGluR activation and desensitization

11. 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

12. Effects of glutamate-induced excitotoxicity

13. Generalised model of ionotropic glutamate receptor (iGluR)

14. 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 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.

15. 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.

17. AMPA receptor Kainate receptors NMDA receptor

18. 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

21. GABA receptors GABA - major inhibitory NT in the mammalian CNS GABA receptors are pentameric in structure 3 classes GABAA and GABAC receptors are ionotropic, GABABreceptors are metabotropic

22. GABAA receptor binding sites Benzodiazepine – allosteric agonist - tranquilisers / anticonvulsants Barbiturates – prolong action of GABA - anaesthetics / hypnotics

23. Imbalances in NT levels green agonist (mimic) blue increases the transmitter (reuptake inhibitors etc.) red antagonist orange decreases the transmitter (inhibits release etc.)