Metabotropic Receptors

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Metabotropic Receptors

• Neurotransmitter gated (Glutamate, GABA, most
  other neurotransmitters)
• G-protein linked
• Various signaling pathways
• -/ Adenylate cyclase
• PIP2 hydrolysis/IP3/Calcium release
• Ion channel modulation (Ca, K)
• Modulate excitability

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Glutamate/GABA Family of Metabotropic Receptors
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Structural Features of Metabotropic Glutamate
Receptors
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mGluR Classification

• Group I-mGluR1 and mGluR5
• coupled to PIP2 hydrolysis/Ca release, ion
  channel modulation
• primarily post-synaptic
• Group II-mGluR 2 and mGluR3
• inhibit adenylate cyclase, ion channel modulation
• primarily presynaptic
• Group III-mGluR 4, 6 (retinal bipolar cells),7, 8
• inhibit adenylate cyclase
• primarily presynaptic

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Brain distribution of mGluR receptors
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Location and Function of mGluRs
Group I
Group II
Group III
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mGluR Pharmacology

• Group I Selective Agonists
• Quisqualate-most potent-also activates AMPA
  receptors
• DHPG-mGluR1 and 5
• Group II Selective Agonists
• LY354740-mGluR2/3 (low nM), active systemically

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mGluR Pharmacology

• Group I Antagonists
• mGluR1-CPCCOEt
• mGluR5-MPEP
• Group II Antagonists
• LY341495-at low nM concentrations
• Group III Antagonists
• Least developed
• MPPG, CPPG

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Effects of mGluR1 and mGluR5 Activation on Cai
and Holding Current
TTX-tetrodotoxin DHPG-Group I agonist MPEP-mGluR5
antagonist LY367385-mGluR1 antagonist
Hippocampal slice, CA1 pyramidal neurons
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Group I mGluRs Regulate IAHP
IAHP arises from activation of Ca activated K
channels (SK) that help repolarize neurons after
depolarization Inhibition of IAHP increases
excitability
MPEP-mGluR5 antagonist
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Group I mGluRs Enhance NMDA Currents Evoked
by Agonist Application
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mGluR5 KO Mice Show Attenuated Response to Cocaine
locomotor activity following cocaine-no
activation in KO mice
mGluR5 KO do not SA cocaine The mGluR5
antagonist MPEP reduces SA in WT mice
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mGluR5 KO Mice Show Normal DA Response to Cocaine
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Group II and III mGluRs Mediate Presynaptic
Inhibition of NT Release

• Effects are pertussis toxin sensitive
• At least 3 mechanisms responsible
• Block of presynaptic calcium channels
• Enhanced potassium current
• Direct effect on release machinery
• May function as autoreceptors on glutamate
  terminals in some brain areas and as
  heteroreceptors on non-glutamatergic terminals

EPSCs in Globus pallidal neurons DCG-IV Group II
selective L-AP4-Group III selective
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GABAB Receptors

• First suspected in 1981 l-baclofen induced
  responses not blocked by bicucculine, the GABAA
  antagonist
• Expression cloning in oocytes not successful as
  with mGluRs
• cDNA isolated in 1997

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GABAB Receptors-Structure and Function

• 960 amino acids
• 7 transmembrane domains-long intracellular
  C-terminus
• Two major subtypes BR1 and BR2-probably assemble
  as homodimers or heterodimers
• Each have splice variants

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GABAB Pharmacology

• GABAB agonists
• Baclofen (?4-chlorophenyl GABA)
• Muscle relaxant-reduce motor neuron activity via
  presynaptic inhibition
• Used to treat spasticity associated with
  brain/spinal cord injury, cerebral palsy,
  multiple sclerosis)
• Also used as anti-nociceptive-reduces release of
  substance P, glutamate may reduce craving for
  drugs of abuse
• GABAB Antagonists
• Phaclofen, 2-OH-saclofen-low affinity
• Enhance cognitive performance in animals
• Reduce absence seizures

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GABAB Potentiation of GirK Channels Expressed in
Oocytes
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Neurophysiology of GABAB ReceptorsGABAB Knockouts

• Regulate Ca and K channels
• Presynaptic-reduce NT release through interaction
  with N/P/Q calcium channels
• Post-synaptic-hyperpolarize via GirK activation

Baclofen-GABAB agonist 54626-GABAB
antagonist Adenosine-Agonist DAMGO-opioid agonist