Receptors and transduction mechanisms II

• Chapter 12 – The Neuron by Levitan and Kacsmarek

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 receptors (G-protein-coupled receptors, GPCR

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)

an intracellular second messenger influences ion channel activity

Second messenger-mediated receptor-channel coupling

SLOWINDIRECT

GPCR coupling

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

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

Allows a constant modification temporal information processing

Generic GPCR structure

Why 7TMs?

Human -adrenergic receptor

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

Intracellular signal transduction by the PIP2 cascade

mGluR1/5

Homer

Ca2+

IP3R

GPCR coupling can produce diverse responses

• Depends on type of G-protein and type of effector

• Single ligand can activate multiple GPCR pathways

• Depends on receptor numbers

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 ahalf-maximal stimulation of effector

Brought about by receptor phosphorylation

Some types of GPCR

group I, II and III

metabotropic glutamate

(mGlu) receptors

Trends in Pharmacological Sciences Volume 25, Issue 5 , May 2004, Pages 265-272

Nature Reviews Drug Discovery 4, 131-144 (2005)Metabotropic glutamate receptors as novel targets for anxiety and stress disorders

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

A metabotropic glutamate (mglu)

receptor associated with a heterotrimeric G protein

Trends in Pharmacological Sciences Volume 22, Issue 3 , 1 March 2001, Pages 114-120

Residues that control the coupling of metabotropic glutamate (mglu) receptors to G proteins

Human -adrenergic receptor

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

group I, II and III metabotropic glutamate (mGlu) receptors neurotransmitter pathways implicated in mediating the actions of drugs of abuse (rat brain)

1) G protein-mediated receptor-channel coupling. 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.

2) Second messenger-mediated receptor-channel coupling: an intracellular second messenger influences ion channel activity.

3) With second messenger coupling the binding of a single transmitter can activate many channels, activate several classes of channels and affect other cellular processes not associated with ion channels.

SLOWINDIRECT

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