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Neurotransmission and Signal Transduction

Neurotransmission and Signal Transduction. Objectives Review aspects of chemical transmission and intracellular signalling in the brain Role of neurotransmitter/signal transduction abnormalities in selected neurological/psychiatric disorders Rational pharmacology for nervous system disorders

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Neurotransmission and Signal Transduction

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  1. Neurotransmission and Signal Transduction • Objectives • Review aspects of chemical transmission and intracellular signalling in the brain • Role of neurotransmitter/signal transduction abnormalities in selected neurological/psychiatric disorders • Rational pharmacology for nervous system disorders • Prediction of side-effect profile Paul Glue

  2. 2…releasing neurotransmitter into synapse... 1: Presynaptic neuron fires... 6…which may lead to cell firing; inhibition of firing; genome activation, peptide production etc…. 3…transmitter interacts with a post-synaptic receptor which may... 4…activate second messenger pathways…. 5….open an ion channel…. Basic Neurotransmission 7…which may translate into perception; memory; emotion; autonomic homeostasis; endocrine response etc…. 8…and in pathological states may translate into depression, seizures, neurodegeneration, etc….

  3. Neurotransmission • Based on anatomy of neuronal pathways • Based on diffusion of chemical signals • signalling may extend beyond the site of release to adjacent synapses • Based on speed of response • fast: glutamate (+); GABA (-) • slow/modulatory: serotonin, norepinephrine, neurohormones • Based on neuronal responses • chemical signal from proximal neuron may produce : • nerve firing/inhibition of firing • increased activity of second messengers • gene transcription • increased/decreased receptor density/sensitivity • increased/decreased synaptic connections • (synaptic plasticity)

  4. Characteristics of 4 Major Receptor Types

  5. Ligand-Gated Ion Channels • - Agonist-regulated, ion-specific, membrane spanning channels • Passage of ions alters membrane potential/ionic composition • Made up of subunits • Examples: Nicotinic cholinergic, GABA-A, glycine, glutamate, aspartate, 5-HT3 receptors

  6. G-Protein Coupled Receptors - 7 transmembrane-spanning -helices - Associated with trimeric GTP-binding regulatory proteins - Agonist binding to extracellular domain - GTP activates G-protein, which then activates specific effector proteins - Individual cells can express up to 20 GPCRs Examples: NE, 5-HT, DA, histamine, opioids, (>750) Video clip

  7. Arrestin binds to the phosphorylated C-terminal tail Receptor-G protein interaction is prevented and receptor activity is halted c-Src (tyrosine kinase) binds to arrestin Arrestin binds to clathrin (vesicular protein) c-Src phosphorylates dynamin; endocytosis of receptor commences A G-protein receptor kinase phosphorylates the receptor’s C-terminal tail G-Protein complex is activated by a GDPGTP switch in Gα subunit Activated Gα and β/γ subunits move to regulate effectors Agonist binds to G-Protein-coupled receptor Gα GTP β β β γ γ γ Gα GTP Gα GTP Effector Effector Effector Receptor may be reinserted in membrane… β β γ γ β β β β β β β γ γ γ γ γ γ γ β γ Gα GDP Gα GDP Effector Effector Dyn Dyn Dyn Dyn Gα GDP Gα GDP Gα GTP Gα GTP Gα GTP Gα GTP Gα GTP Gα GTP Effector Effector Effector Effector Effector Effector Effector Effector Dyn Dyn Endocytosis is complete. Agonist dissociates and Receptor is dephosphorylated Endocytosis is complete. Agonist dissociates and Receptor is dephosphorylated P P P P P P c-Src c-Src P P Or may remain in vesicle in cytoplasm in an inactive state…. Arrestin Arrestin P G effects on: Gαs:  adenylyl cyclase Adenylyl cyclase Gαi:  adenylyl cyclase Phospholipase C Gαo:  Ca++ currents PI-3-kinase Gαq:  phospholipase C Inward-rectifier Gα13:  RHO GTP exchange K+ currents catalyst P c-Src β γ Arrestin Gα GTP Effector GRK P GTP c-Src Or may be degraded by lysosomes Arrestin GRK GDP P c-Src Arrestin Intracellular Signal Transduction VIDEO

  8. Intracellular Signaling • Post-receptor signal transduction occurs via networks of signaling proteins (2o and 3o messengers) • transform multiple external stimuli into appropriate cellular responses. • Molecules in this network form ordered biochemical pathways • signal propagation occurs through the sequential protein-protein and small molecule-protein interactions. • Signaling components are organized into macromolecular assemblies (adapter proteins) • organize signaling pathways into distinct functional entities • critical for efficiency and specificity of signaling • various levels of complexity (simple to complex multi-domain proteins)

  9. Transmitter Transmitter activates receptor Receptor activates G-protein GTP GDP GTP GDP GTP GDP G-protein stimulates adenylyl cyclase to convert ATP to cAMP AC AC AC ATP ATP ATP cAMP cAMP cAMP PKA PKA PKA cAMP cAMP cAMP cAMP activates protein kinase A PKA phosphorylates K channels Signal Amplification Cascade

  10. Synaptic Plasticity • Historical View: • Synapses and overall neuronal structure relatively fixed. • Learning and other mental processes occurred via adjusting the threshold and firing rate between the synapses • Contemporary View: • Neuronal signaling and responsiveness are highly dynamic and adaptive • Changes may occur in response to developmental or experiential input • Changes may occur at multiple levels (molecular, transcriptional, cellular)

  11. Some Of The Major Intracellular Signalling Pathways Involved In Regulating Neural And Behavioral Plasticity

  12. Transduction at multiple levels - Vision

  13. Examples of Dopaminergic Plasticity • Desensitization (agonists): • Rapid loss of euphoric effects of cocaine • Loss of efficacy of PD treatment over time (?or due to disease progression) • Sensitization (agonists) • Increased dendrite density in N Acc, PFC after chronic cocaine/amphetamine • May explain phenomenon of behavioral sensitization • Sensitization (antagonists) • Tardive dyskinesia possibly caused by striatal D2 hypersensitivity, following chronic neuroleptic treatment

  14. NE/5HT plasticity • Desensitization • Short term use of antidepressants • Reduction of incidence/severity of earl;y side effects (GI symptoms, insomnia, anxiety) • Chronic administration of antidepressants • Postsynaptic receptors – therapeutic • Abrupt antidepressant withdrawal • Presynaptic autoreceptors – possible cause of withdrawal symptoms after stopping antidepressants • Synaptic/neuronal growth • Serotonin depletion reduces synaptic density •  hippocampal neurogenesis by antidepressants •  dendritic growth by lithium

  15. Other plasticity examples… • Tolerance to alcohol and …. • Alcohol withdrawal and …. • Acute BDZ tolerance (waking post O/D) vs chronic tolerance • Tolerance to opioids • Hypertensive rebound after stopping clonidine

  16. Conclusions • Chemical neurotransmission and subsequent signal transduction are the main processes for neuronal communication • Adaptive, plastic process • Role of specific neurotransmitters in selected nervous system disorders • Biochemical basis for neurological and psychiatric disorders • Choice of rational pharmacotherapy for nervous system disorders • Also may predict side-effect profile of existing and new treatments • Range of potential therapies will expand as our understanding of central transmission/signal transduction becomes more sophisticated

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