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Receptors and transduction 2

Receptors and transduction 2. Dr. MV Hejmadi. References: Chapter 12 – Neuron by Levitan & Kaczmarek OR Chapter 6 – Neuroscience by Purves et al Metabotropic glutamate receptors by AJ Doherty and GL Collingridge www.els.net.

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Receptors and transduction 2

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  1. Receptors and transduction 2 Dr. MV Hejmadi References: Chapter 12 – Neuron byLevitan & KaczmarekOR Chapter 6 – Neuroscience byPurves et al Metabotropic glutamate receptors by AJ Doherty and GL Collingridge www.els.net

  2. 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 In the case shown here, binding of neurotransmitter (NT) to its receptor activates a G protein that then interacts with an ion channel, causing it to open

  3. Second messenger-mediated receptor-channel coupling an intracellular second messenger influences ion channel activity

  4. Why are GPCR responses slower and longer lasting than iR responses? Allows a constant modification of temporal information processing

  5. GPCR coupling can produce diverse responses • Depends on type of G-protein and type of effector • Single ligand can activate multiple GPCR pathways • alter receptor numbers (synthesis/turnover) • Can result in desensitisation

  6. Responses can be regulated by altering receptor numbers

  7. Desensitisation is a mechanism of decreasing the cellular response to transmitter Desensitisation is defined as the increase in agonist required to produce a half-maximal stimulation of effector Physical removal by receptor-mediated endocytosis Brought about by receptor phosphorylation

  8. Metabotropic receptor types

  9. Generic GPCR structure Why 7TMs? TiPs (2001)22,(3) 114-120

  10. Human b-adrenergic receptor TMIII – Asp (D113) binds to N-terminus of epinephrine TMV – two Ser (S204 +S207) binds to 2 OH termini

  11. Metabotropic glutamate receptors • Distinct from other GPCRs • Act via trimeric guanine-nucleotide binging protein (G protein) • Implicated in several conditions like anxiety and stress disorders (alternative targets to GABAaR), addiction etc

  12. mGluR families Divided into 3 groups based on their sequence homology, signal transduction mechanisms and pharmacology (stimulation by phospholipase C) (inhibition of adenylcyclase) (inhibition of adenylcyclase)

  13. mGluR signalling mechanisms Other signalling mechanisms mGluR6 coupled to cGMP to induce hyperpolarisation stimulates arachidonic acid production via PLC- PLA2 cascade Modulate voltage-gated and ligand-gated ion channels

  14. Physiological roles of mGluR • Synaptic transmission in the brain (group I) • Synaptic transmission in the retina (mGlu6) • Modulation of transmitter release (function as autoreceptors) • Long term potentiation / depression (LTP/LTD) implicated in learning & memory • Neurological disorders – excitoxicity, pain, anxiety, epilepsy, schizophrenia

  15. Postsynaptic glutamate receptor signaling pathways. Science 25 October 2002:Vol. 298. no. 5594, pp. 776 - 780

  16. Targets galore for glutamate!

  17. Synaptic location and function of mGluR Presynaptic mGluR modulate Glu release Post synaptic mGluR Regulate synaptic transmission Implicated in LTP/LTD (mGluR group I and II) Nature Reviews Drug Discovery 4, 131-144 (2005)

  18. neurotransmitter pathways implicated in mediating the actions of drugs of abuse (rat brain)

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