Transcript DHPG
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 Glutamate/GABA Family of Metabotropic Receptors Structural Features of Metabotropic Glutamate Receptors 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 Brain distribution of mGluR receptors Location and Function of mGluRs Group I Group II Group III 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 mGluR Pharmacology • Group I Antagonists – mGluR1-CPCCOEt – mGluR5-MPEP • Group II Antagonists – LY341495-at low nM concentrations • Group III Antagonists – Least developed – MPPG, CPPG 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 Group I mGluR’s 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 Group I mGluRs Enhance NMDA Currents Evoked by Agonist Application 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 mGluR5 KO Mice Show Normal DA Response to Cocaine 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 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 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 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 GirK 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 GirK activation Baclofen-GABAB agonist 54626-GABAB antagonist Adenosine-Agonist DAMGO-opioid agonist