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