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Receptors and transduction 2 References: Chapter 12 – Neuron by Levitan & Kaczmarek OR Chapter 6 – Neuroscience by Purves et al 1)Metabotropic glutamate receptors by AJ Doherty and GL Collingridge www.els.net Dr. MV Hejmadi
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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 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
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an intracellular second messenger influences ion channel activity Second messenger-mediated receptor-channel coupling
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Why are GPCR responses slower and longer lasting than iR responses? Allows a constant modification of temporal information processing
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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
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Responses can be regulated by altering receptor numbers
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Desensitisation is a mechanism of decreasing the cellular response to transmitter Physical removal by receptor- mediated endocytosis Desensitisation is defined as the increase in agonist required to produce a half-maximal stimulation of effector Brought about by receptor phosphorylation
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Metabotropic receptor types
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Generic GPCR structure Why 7TMs? TiPs (2001)22,(3) 114-120
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Human -adrenergic receptor TMIII – Asp (D113) binds to N-terminus of epinephrine TMV – two Ser (S204 +S207) binds to 2 OH termini
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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
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mGluR families Divided into 3 groups based on their sequence homology, signal transduction mechanisms and pharmacology (stimulation by phospholipase C) (inhibition of adenylcyclase)
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Other signalling mechanisms mGluR 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
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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
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Science 25 October 2002: Vol. 298. no. 5594, pp. 776 - 780 Postsynaptic glutamate receptor signaling pathways.
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Targets galore for glutamate!
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Synaptic location and function of mGluR Nature Reviews Drug Discovery 4, 131-144 (2005) Presynaptic mGluR modulate Glu release Post synaptic mGluR Regulate synaptic transmission Implicated in LTP/LTD (mGluR group I and II)
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neurotransmitter pathways implicated in mediating the actions of drugs of abuse (rat brain)
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