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 Dr. 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 SLOW INDIRECT

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 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

Metabotropic receptor types

Generic GPCR structure Why 7TMs? TiPs (2001)22,(3)

Human  -adrenergic receptor TMIII – Asp (D113) binds to N-terminus of epinephrine TMV – 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 families Divided into 3 groups based on their sequence homology, signal transduction mechanisms and pharmacology (stimulation by phospholipase C) (inhibition of adenylcyclase)

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

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

Science 25 October 2002: Vol no. 5594, pp Postsynaptic glutamate receptor signaling pathways.

Targets galore for glutamate!

Synaptic location and function of mGluR Nature Reviews Drug Discovery 4, (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)