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Synaptic transmission Module 725 Lecture 2 Aim Why do we need synapses? To know about chemical synapses diversity flexibility mechanisms Overview Neurotransmitters Synaptic structure Transmitter release Transmitter breakdown/uptake Ionotropic receptors Neurotransmitters Acetylcholine amino-acids glutamate GABA peptides FMRFamide NO (see next week) Synaptic structure Neuromuscular junction CNS synapses Common features transmitter stored in vesicles receptors on postsynaptic membrane cell-cell signalling to organise synapse Neuromuscular junction CNS synapses Overview of physiology Simulation at http://lessons.harveyproject.org/developm ent/nervous_system/cell_neuro/synapses/ release.html Transmitter release calcium-dependent vesicle cycling - or kiss and run Calcium domains squid giant synapse use n-aequorin-J as Ca indicator Calcium-dependency Calcium entry very near vesicle! micro or even nano-domains synaptotagmin as Ca sensor ? Vesicle cycling Conventional view need recycling because no evidence of increase in membrane area e.g. capacitance measurements Vesicle proteins synaptobrevin & SNAP-25 anchor vesicle membrane to plasma membrane syntaxin helps in conformational change synaptotagmin as Ca sensor Synaptotagmin calcium sensor arginine in C2A and C2B domains Exocytosis free energy barriers need to be overcome during fusion Endocytosis Clathrin coats “empty” vesicles Movie from http://www.hms.harvard.edu/news/clathrin/ Kiss and run testing… testing... capacitance measurements- measures surface area GFP-derivative called synaptophlorin reports pH (vesicles very acid) FM dye which fluoresces only in membrane Summary so far transmitter put into vesicles vesicle release is Ca-dependent major protein players include synaptotagmin SNARE clathrin Breakdown or uptake? esterase (ACh, peptides) transport - mostly into glia (amino acids) Re-uptake 12 membrane spanning regions co-transport using Na gradient Uptake inhibitors major drugs cocaine - block serotonin & dopamine reuptake Prozac - selective serotonin reuptake inhibitors serotonin cocaine prozac Summary so far transmitter put into vesicles vesicle release is Ca-dependent transmitter recycled after breakdown direct pump for reuptake Ionotropic receptors Ionotropic receptors have an integral channel which opens when receptor binds Metabotropic receptors activate a second messenger internally Important ionotropic receptors include nicotinic ACH receptor glutamate (NMDA, AMPA, Kainate) GABA Nicotinic ACh receptor 2 a, one each of b, g , d ACh binds to a - need 2 ACh to open channel Nicotinic ACh receptor highly conserved residues binding ACh Glutamate receptor 2 a, one each of b, g , d glu binds to a - need 2 glu to open channel NMDA receptors also need glycine Multiple glu receptors Named after agonists NMDA receptors (I) blocked by Mg, except at depolarised voltages need glycine as cofactor squirt a-a and see cell current NMDA receptors (II) may provide slow component to synapse stimulate presynaptic neuron and see cell current AMPA & Kainate receptors May both be used at same synapse stimulate presynaptic cell and record voltage APV blocks NMDA, GYKI blocks AMPA LY293558 blocks kainate GABAA receptor GABAA - drug action Benzodiazepines e.g. Valium (=diazepam) hypnotic, anxiolytic, anticonvulsant, myorelaxant and amnesic Barbiturates e.g. pentobarbital sedative action GABAA - diazepam control longer openings in bursts DZ Summary transmitter put into vesicles vesicle release is Ca-dependent transmitter recycled after breakdown direct pump for reuptake ionotropic receptors great diversity homologous subunits Synaptic transmission major drug target