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Neurotransmission and Signal Transduction Paul Glue 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 Basic Neurotransmission 2…releasing neurotransmitter into synapse... 1: Presynaptic neuron fires... 3…transmitter interacts with a post-synaptic receptor which may... 4…activate second messenger pathways…. 6…which may lead to cell firing; inhibition of firing; genome activation, peptide production etc…. 5….open an ion channel…. 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…. 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 (synaptic plasticity) • increased/decreased synaptic connections Characteristics of 4 Major Receptor Types Receptor Ligand-gated ion channel Timescale Effector Milliseconds Channel Coupling Example Direct Nicotinic AChR G-proteinSeconds coupled receptor Channel/ enzyme G-protein Muscarinic AChR Kinase-linked receptor Enzyme (tyrosine kinase) Direct or indirect Insulin Gene transcription Via DNA Thyroid, estrogen Minutes Nuclear receptor Hours Ligand-Gated Ion Channels - Agonist-regulated, ionspecific, 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 G-Protein Coupled Receptors 7 transmembrane-spanning helices - Associated with trimeric GTPbinding 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 Intracellular Signal Transduction Arrestin binds to the phosphorylated C-terminal tail Arrestin binds to clathrin (vesicular protein) Receptor-G protein interaction is prevented G-Protein A G-protein complex receptor is kinase activated phosphorylates by a c-Src phosphorylates endocytosis Activated Gα and β/γ subunits receptor activity isdynamin; haltedreceptor Agonistand binds to G-Protein-coupled GDPGTP the receptor’s switch C-terminal in Gα tail subunit of receptor commences move to regulate effectors c-Src (tyrosine kinase) binds to arrestin γ Gα β VIDEO GTP Receptor may be reinserted in membrane… β β γ γ β γ Gα Gα Gα Dyn DynDyn Effector Effectoris complete. Endocytosis Dyn Dyn P P Gα Effector GTP GDP GTP c-Src P P P P GTP GTP dissociates Or mayAgonist remain in vesicle inand Receptor is dephosphorylated cytoplasm in an inactive state…. P G Gαs: adenylyl cyclase c-Src effects on: GDP ArrestinAdenylyl cyclase GRK Gαi: adenylyl cyclase Phospholipase C Gαo: Ca++ currents P PI-3-kinase Gαq: phospholipase C c-Src GTP Or may be degraded by lysosomes ArrestinInward-rectifier Gα13: RHO GTP exchange K+ currents catalyst GRK Arrestin P P Arrestin c-Src 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) Signal Amplification Cascade Transmitter Transmitter activates receptor Receptor activates G-protein GTP G-protein stimulates adenylyl cyclase to convert ATP to cAMP GDP GTP GDP AC ATP cAMP PKA cAMP PKA phosphorylates K channels GTP AC ATP cAMP activates protein kinase A GDP AC ATP cAMP PKA cAMP cAMP PKA cAMP 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) Some Of The Major Intracellular Signalling Pathways Involved In Regulating Neural And Behavioral Plasticity Transduction at multiple levels - Vision Environmental stimulus Specific receptor and second messenger Sensory nerve Primary cortex Light waves G-protein associated with rhodopsin in rods/cones Depolarization of neurons in optic N Occipital cortical neurons Secondary cortices Localized processing of specific categories (shape, movement, color, faces) Organization of images in temporal lobes. Memory and affective input DLPFC (executive functioning, planning, decision making) Association cortices Higher processing 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 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 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 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