Metabotropic Receptors Neurotransmitter gated Glutamate GABA most other

Metabotropic Receptors • Neurotransmitter gated (Glutamate, GABA, most other neurotransmitters) • G-protein linked • Various signaling pathways – -/+ Adenylate cyclase – PIP 2 hydrolysis/IP 3/Calcium release – Ion channel modulation (Ca++, K+) • Modulate excitability

Glutamate/GABA Family of Metabotropic Receptors

Structural Features of Metabotropic Glutamate Receptors

m. Glu. R Classification • Group I-m. Glu. R 1 and m. Glu. R 5 – coupled to PIP 2 hydrolysis/Ca++ release, ion channel modulation – primarily post-synaptic • Group II-m. Glu. R 2 and m. Glu. R 3 – inhibit adenylate cyclase, ion channel modulation – primarily presynaptic • Group III-m. Glu. R 4, 6 (retinal bipolar cells), 7, 8 – inhibit adenylate cyclase – primarily presynaptic

Brain distribution of m. Glu. R receptors

Location and Function of m. Glu. Rs Group III

m. Glu. R Pharmacology • Group I Selective Agonists – Quisqualate-most potent-also activates AMPA receptors – DHPG-m. Glu. R 1 and 5 • Group II Selective Agonists – LY 354740 -m. Glu. R 2/3 (low n. M), active systemically

m. Glu. R Pharmacology • Group I Antagonists – m. Glu. R 1 -CPCCOEt – m. Glu. R 5 -MPEP • Group II Antagonists – LY 341495 -at low n. M concentrations • Group III Antagonists – Least developed – MPPG, CPPG

Effects of m. Glu. R 1 and m. Glu. R 5 Activation on Cai and Holding Current TTX-tetrodotoxin DHPG-Group I agonist MPEP-m. Glu. R 5 antagonist Hippocampal slice, CA 1 pyramidal neurons LY 367385 -m. Glu. R 1 antagonist

Group I m. Glu. R’s Regulate IAHP arises from activation of Ca++ activated K+ channels (SK) that help repolarize neurons after depolarization Inhibition of IAHP increases excitability MPEP-m. Glu. R 5 antagonist

Group I m. Glu. Rs Enhance NMDA Currents Evoked by Agonist Application

m. Glu. R 5 KO Mice Show Attenuated Response to Cocaine locomotor activity following cocaine-no activation in KO mice m. Glu. R 5 KO do not SA cocaine The m. Glu. R 5 antagonist MPEP reduces SA in WT mice

m. Glu. R 5 KO Mice Show Normal DA Response to Cocaine

Group II and III m. Glu. Rs 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-AP 4 -Group III selective

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 m. Glu. Rs • c. DNA isolated in 1997

GABAB Receptors-Structure and Function • 960 amino acids • 7 transmembrane domains-long intracellular C-terminus • Two major subtypes BR 1 and BR 2 -probably assemble as homodimers or heterodimers • Each have splice variants

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

GABAB Potentiation of Gir. K Channels Expressed in Oocytes

Neurophysiology of GABAB Receptors GABAB Knockouts • • • Regulate Ca++ and K+ channels Presynaptic-reduce NT release through interaction with N/P/Q calcium channels Post-synaptichyperpolarize via Gir. K activation Baclofen-GABAB agonist 54626 -GABAB antagonist Adenosine-Agonist DAMGO-opioid agonist