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Metabotropic Neurotransmitter
Receptors
Dopamine Receptors
Dopamine receptors
• D1, D5 types
• D1 highest expressed DA receptor
– Coupled to Gas
• D2,3,4 types
• D2 is the site of action for anti-psychotic drugs
– Coupled to Gai and Gao
• Primary AC in striatum is AC5
– Activated by Gas and PKC
– Inhibited by Gai/o and Ca2+
D2 autoreceptor
• D2 can be alternatively spliced to D2s and D2l
• D2s acts as the inhibitory pre-synaptic
autoreceptor
– Inhibits synthesis and release of DA
• D2l functions as an inhibitory post-synaptic
receptor
Adrenergic Receptors
• a1-adrenergic receptors
– 3 types, all coupled to Gaq/11 (PLC pathway)
• a2-adrenergic receptors
– 3 types, coupled to Gai/o (inhibit AC)
– Found pre-synaptically, acts as autoreceptor
• b-adrenergic receptors
– 3 types, coupled to Gas (activate AC)
– Often found on glia, where they reduce glutamate
uptake and regulate glucose utilization
Functional Roles of adrenergic
receptors
• Hypothalamic
– A1 in MPO area mediate wakefulness
• Amygdala and HPC
– A1 and B receptor activation promotes long term
memory consolidation
– A2 activation enhance working memory in PFC
– A1 activation in PFC inhibits its function
CA Receptor Regulation
• Agonist induced down regulation
– Receptors are internalized after prolonged
treatment with agonists
• Reuptake inhibitors
• Drugs like amphetamine
• Denervation Supersensitivity (203 lab)
– Physical ablation or chemical antagonism of
receptor activation leads to increased receptor
density and sensitivity
Muscarinic Ach Receptors
mAchR localization
• M1-abundant post-synaptic (dendritic)
receptor in the brain
• M2 enriched in thalamus and brainstem, low
levels elsewhere
– Pre-synaptic autoreceptor
• M3 low levels in cortex and HPC
• M5 low levels in VTA, SN midbrain
• M4 high levels in striatum (pre-synaptic)
Implications for disease
• AD-loss of cholinergic neurons
• Schizophrenia- reduced levels of M1 and M4
– Genetic and pharmacological links
• Parkinson’s disease
– Links to nicotine protection
– Regulation of pre-synaptic DA release
– Balance of Ach and DA in Striatum regulates
movement
• Drug Addiction-M5 antagonists in VTA
Serotonin Receptors
Serotonin Receptors
5-HT1A
• Gi/o coupled
• Cortex and hippocampus
• Post-synaptic and somatodendritic
autoreceptor functions
– As autoreceptors, mechanism is via activation of
K+ channels
• Function in feeding, sexual behaviors, and
body temperature, ACTH release
• Agonists of 5-HT1A treat anxiety, and perhaps
depression and schizophrenia too
5-HT2 Family
• Gq coupled
• 5-HT2A post-synaptic receptor found highest
in PFC on both GABA and Glutamate neurons
• Homeostatic functions (temperature)
• Roles in cognition and mental illness
– Antagonists are anti-psychotic
– Agonists are hallucinogenic
5-HT 4,6,7 receptors
• Gs coupled
• 5-HT4
– Multiple splice isoforms
– Not well studied
• 5-HT6
– Target of anti-psychotic drugs and anti-depressants
(striatum)
– Antagonists increase Ach transmission, improve
learning and memory
• 5-HT7
– Sleep, circadian rhythms and mood (SCN)
– Target of anti-psychotic drugs
Metabotropic Glutamate Receptors
Gi
Gq
Functional Roles for mGluR
• All 3 classes inhibit L-type voltage sensitive
Ca2+ channels
• mGluR activation also closes K+ channels,
leading to slow repolarization (prolong
excitation) HPC and cortex
• Opposite effect in cerebellum
• Pre-synaptic mGluRs are inhibitory-on both
Glutamate and GABA neurons (Ca2+ channel)
Studies in knock-out mice
• mGlu1 -/- mice-cerebellar ataxia
– mGlu1 necessary for pruning of climbing fiberPurkinje cell synapses during development
– LTD is defective, poor motor learning
• mGlu2 -/- mice- impaired LTD in HPC
Metabotropic GABA receptors
• 2 members, R1 and R2, have been cloned
• Function as a dimer, R1 binding GABA, R2
binding the G protein
• 4 known associated subunits regulate
localization, function, and pharmacology
• Inhibitory
– Open K+ channels
– Block Ca2+ channels (presynaptic inhibition)
– Inhibit AC