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181lec5 - Psych 181 Dr Anagnostaras Lecture 5 Synaptic...

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Unformatted text preview: Psych 181: Dr. Anagnostaras Lecture 5 Synaptic Transmission Introduction to synaptic transmission Synapses (Gk., to clasp or join) Site of action of most Site psychoactive drugs psychoactive QuickTimeª and a decompressor are needed to see this picture. 6.5 Synapses Know basic terminology: q Soma q Axon q Dendrite q Synaptic vesicles q Synaptic cleft q Postsynaptic q Presynaptic q Glia 7 234 8 5 6 1 6.2 Synapses Dendrites & Dendrites spines spines 3.10 Synapses Types of cell-cell junctions Tight junctions q membranes fused Gap junctions q close juxtaposition (2-4 nm) q electrical synapse Chemical synapses q synaptic cleft (20-30 nm) q polarized Multiple types of synapses Spherical agranular Spherical granular vesicles Vesicle varieties + Reciprocal junction Flattened vesicles - 6.3 6.4 Multiple types of synapses Multiple patterns of connectivity q Axodendritic q Dendrodendritic q Axoaxonic q Axosomatic q etc. 6.1 Steps in synaptic transmission q Synthesis q Transport q Storage q Release q Inactivation Release Excitation-secretion coupling q q q q q q q q Depolarization Open voltage-gated Ca++ channels ++ Ca++ influx influx ++ Bind to Ca++ -calmodulin protein kinase -calmodulin Phosphorylation of synapsin I Movement of vesicles to release site Exocytosis Diffusion Exocytosis 6.17 Inactivation HVA Reuptake q transporters Extracellular DOPAC DOPAC Monoamine oxidase Tyrosine Cytoplasmic DA Releasable DA Dopamine transporter Extracellular DA COMT 3-MT Enzymatic degradation q metabolism q excretion q cycling DOPA 8.13 Sample question In which of the following are the events listed in the correct temporal order (i.e., the temporal order associated with excitation-secretion coupling)? (a) Depolarization > calcium influx > phosphorylation of synapsin > activation of calcium-calmodulin protein kinase > exocytosis (b) Depolarization > calcium influx > activation of calcium-calmodulin protein kinase > phosphorylation of synapsin > reuptake > exocytosis (c) Exocytosis > phosphorylation of synapsin > calcium influx > activation of calcium-calmodulin protein kinase > depolarization > calcium influx (d) Enzymatic degradation > exocytosis > activation of calciumcalmodulin protein kinase > phosphorylation of synapsin > calcium influx > depolarization (e) Depolarization > calcium influx > activation of calcium-calmodulin protein kinase > phosphorylation of synapsin > exocytosis > enzymatic degradation Neurotransmitters Two major types: “Classical” q small water soluble molecules with amine q formed from dietary precursors Neuropeptides q protein synthesis Neurotransmitters Phenylethylamines q DA, NE, E, tyramine, etc. 5-HT, tryptamine, melatonin, etc. 5-HT, Indoleamines q Cholinergics Cholinergics Amino acids GABA, glutamate, etc. GABA, Amino Neuropeptides q Enkephalins, substance P, neurotensin, etc. Nonpeptide hormones Receptors QuickTimeª and a decompressor are needed to see this picture. 6.5 Receptors Classification By Location q GABA Postsynaptic ACH DA Receptors Classification By Location q GABA Postsynaptic q Autoreceptors DA ACH Autoreceptors q q q Presynaptic Somatodendritic Terminal Release-modulating Synthesis-modulating Impulse-modulating GABA q q q ACH DA Receptors Classification: Classification: By Transduction By Mechanism Outside cell Inside cell Drug, transmitter or hormone Receptor Transduction Effector Membrane Receptor Superfamilies 1. Ligand-gated channels q binding site coupled to ion channel q transmitter (or drug) gates the channel q ionotropic receptors Receptor Superfamilies 1. Ligand-gated channels 1. 2. G protein-coupled q receptor coupled to G protein receptor q G protein activates effector protein q metabotropic receptors metabotropic Ligand-gated channels Ligand-gated q q q q Ligand opens channel Ions flow down conc. gradient Extracellular side Rapid Closed Rapidly Binding reversible Open Cytoplasmic side 5.9 Ligand-gated channels Ligand-gated Examples: Nicotinic acetylcholine receptor q coupled to sodium channel q drugs: nicotine, curare GABA receptor A q coupled to chloride channel q drugs: sedative- G protein-coupled receptors G protein-coupled receptors q Large family all Large with 7 membranewith spanning regions Receptor q γ Receptor coupled Receptor α β to G protein, and G Ion channel G protein protein stimulates effector effector Effector enzyme Precursor Second messenger q Slower than Slower ion-coupled ion-coupled 6.22 G protein-coupled receptors Two classes: G protein directly coupled to ion channel q effector is ion channel G protein coupled to 2nd messenger system q effector is enzyme that promotes formation effector of intracellular “second messenger” of G protein-coupled receptors Examples: q Cholinergic muscarinic q GABA B GABA q 5-HT q Opioid q Dopamine q Norepin- Second messengers Are many: q Calcium q cGMP q Phosphoinositides Phosphoinositides α γ β Receptor Ion channel G protein (IP3, diacylglycerol) (IP q cAMP q Effector enzyme Precursor Second messenger cAMP cAMP (cyclic adenosine 3,5(cyclic monophosphate) 1 Receptor cAMP 2 Gs 3 4 Adenylyl cyclase ATP cAMP 5 6 Activate protein kinase 7 (phosphorylate protein) 8 (dephosphorylate by phosphoprotein phosphatase) 9 Biological response 6.22 Protein phosphorylation Changes structure/function of protein Consequence depends on function of protein q ion channel proteins q enzymes q cytoskeletal proteins q vesicular proteins q receptors q gene regulatory proteins Second messengers and protein kinases have many targets from P. Greengard, Science, 2001 from P. Greengard, Science, 2001 Gene regulation Second messengers can alter gene regulation: Second q q q Activate transcription factors Regulate transcription q enhance or supress If enhance - new gene products Gene regulation Two phases of gene activation: Initial phase q induction of immediate-early genes (IEGs) (e.g., cfos, c-jun, zif-268, etc.) (e.g., cfos c-jun zif-268 q protein products initiate 2nd phase Second phase q induction of “late-onset genes” q products that alter cellular function Gene regulation by cAMP Agonist Receptor Plasma membrane R= regulatory subunit C= catalytic subunit Transcription factor: CREB (cAMP response element binding protein) Nuclear membrane RR AC G ATP cAMP R R Protein C C kinase A mRNA CREB stimulates gene transcription (eg., IEGs) Nucleus P CC CREB CRE 6.34 Convergence on CREB NGF Plasma membrane Ca2+ Receptor Neurotransmitter or drug Receptor 2nd messengers kinases Ras Ca2+ cAMP Multiple signalling pathways can alter pathways gene transcription gene via same via transcription factor factor CREB-K CaM-K PKA Nuclear membrane CREB Nucleus Gene transcription 6.35 Summary First messengers Neurotransmitters Receptors Drugs of Drugs abuse are very effective in inducing IRGs Coupling factors G proteins Second messengers Diacylglycerol IP3 cAMP cGMP Protein kinases Third messengers Nuclear membrane CREB-like transcription factors Fourth messengers Ca2+ fos-like Transcription factors 6.37 Other genes 6.37 c-fos mRNA Expression Saline Amphetamine Home Novel Sites of drug action 7 234 8 5 6 1 6.2 Sample question Which of the following classes of drug action would Which have in common the effect of increasing synaptic increasing transmission? transmission? (a) facilitation of release; block reuptake; inhibition of synthesis (b) blockade of the release modulating autoreceptor; facilitation (b) of release; receptor agonist of (c) receptor agonist; receptor antagonist; synthesis inhibition (d) reuptake blocker; facilitation of release; receptor antagonist (e) blocks metabolism; block reuptake; inhibits synthesis ...
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