receptors and transduction 2 references: chapter 12 – neuron by levitan & kaczmarek or chapter...
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Receptors and transduction 2Receptors and transduction 2
References:Chapter 12 – Neuron by Levitan & Kaczmarek ORChapter 6 – Neuroscience by Purves et al
1) Metabotropic glutamate receptors by AJ Doherty and GL Collingridge www.els.net
Dr. MV HejmadiDr. 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
SLOWINDIRECT
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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 responsesGPCR 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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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 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 epinephrineTMV – 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 familiesmGluR familiesDivided into 3 groups based on their sequence
homology, signal transduction mechanisms and pharmacology
(stimulation by phospholipase C)
(inhibition of adenylcyclase)
(inhibition of adenylcyclase)
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Other signalling mechanismsOther signalling mechanisms
mGluR signalling mechanismsmGluR signalling mechanisms
mGluR6 coupled to cGMP toinduce hyperpolarisation
stimulates arachidonic acid production via PLC- PLA2 cascade
Modulate voltage-gated and ligand-gated ion channels
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Physiological roles of mGluRPhysiological 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 Postsynaptic glutamate receptor signaling pathways.signaling pathways.
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Targets galore for glutamate!Targets galore for glutamate!
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Synaptic location and function of mGluRSynaptic 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)