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

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

an intracellular second messenger influences ion channel activity

Second messenger-mediated receptor-channel coupling

Why are GPCR responses slower and longer lasting than iR responses?

Allows a constant modification of temporal information processing

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

Responses can be regulated by altering receptor numbers

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

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

Generic GPCR structure

Why 7TMs?

TiPs (2001)22,(3) 114-120

Human -adrenergic receptor

TMIII – Asp (D113) binds to N-terminus of epinephrineTMV – two Ser (S204 +S207) binds to 2 OH termini

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

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)

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

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

Science 25 October 2002:Vol. 298. no. 5594, pp. 776 - 780

Postsynaptic glutamate receptor Postsynaptic glutamate receptor signaling pathways.signaling pathways.

Targets galore for glutamate!Targets galore for glutamate!

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)

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