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 a2-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 Some anti-psychotic drugs antagonize A1 receptors—may act in PFC Many anti-depressants (especially RI class) increase NE levels globally

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 5-HT6 5-HT7 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 fiber-Purkinje cell synapses during development LTD is defective, poor motor learning mGlu2 -/- mice- impaired LTD in HPC

Metabotropic GABAB 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