BISC 307L 2nd Edition Lecture 8 Current Lecture Steps in Chemical Synaptic Transmission 5 steps On the left is the presynaptic terminal The space between the structures is the synaptic cleft On the right is the postsynaptic terminal 1 Synthesis of transmitter T from precursor P Enzymatic synthesis The enzyme that catalyze this can be one or more than one are made in the cell body of the neuron and transported down the axon via the axoplasmic transport system of cytoskeleton microtubules etc Only in the cell body are there organelles necessary for protein synthesis like the nucleus ribosome golgi apparatus etc Things that get transported include proteins and organelles like mitochondria Transmitter synthesis is local usually except for peptide transmitters Keep in mind that each of these steps is a place where transmitter release can be modulated potential targets of therapeutic intervention when you want to mess with cellular function 2 Storage into vesicles Precursor of transmitter is free at first then synthesis then packaged into vesicle Green dot on vesicle is an active transporter Concentration inside is super super high so you need an active transporter to get it in 3 Release of the neurotransmitter Release occurs when action potential comes down the axon and invades the terminal Neurotransmitter release The action potentials are coming downwards Do they actively invade the nerve terminal and all of tis branches It depends In some synapses especially when the presynaptic terminal is huge there are vg Na channels all the way into the branch of the terminal to ensure that the AP invades the entire terminal If the presynaptic terminal is small it doesn t matter much because even if the AP stops actively conducting before the branch you only need a local depolarization and the passive currents ahead of the AP is enough to open the bottom vg Na channels If the length constant of this axon is long relative to the distance between end of axon and presynaptic membrane you don t need an AP Presynaptic membrane at synapse the membrane directly opposite the postsynaptic receptor is highly specialized for transmitter release It is different from the membranes on the sides It has blue blocks which are apparatus necessary for vesicles to dock at the membrane so that with the proper signal they can fuse and release their contents There are also voltage gated Ca channels shown in green that are right next to the release sites As depolarization invades terminal VG Ca channels open and Aa enters the cell down a strong gradient Rises in internal Ca con is toxic to cell so we want a localized increase in Ca conc But the increase causes exocytosis of the NT which diffuses out rapidly Right vesicle Upper half traditional classical understanding of exocytosis It fuses with membrane and becomes part of the membrane and collapses into it and retains its integrity as an island of vesicle membrane and it is internalized once again and recycled Insertion of new membrane pushes old membrane further and further off to the side away from the presynaptic membrane Method 2 Kiss and run vesicle gets close to the membrane fuses with it but doesn t collapse into it Retains its integrity as a vesicle Pore allows NT to diffuse rapidly Vesicle comes off retaining its integrity Back to the steps4 Interaction of transmitter with receptor on postsynaptic membrane In general interaction of transmitter with receptor is ionotropic or metabotropic Can either affect ion channels and cause current flow or metabotropic NT has some metabolic effect on postsynaptic cell due to cell signaling mechanisms we ve been talking about particularly the generation of 2 nd messenger via the pathways we ve mentioned like cAMP IP3 diacylglycerol etc 5 Terminating action of the transmitter Synapse has to be inactivated in order for NS to do its thing again 3 basic methods of inactivation shown by three arrows One pointing to the right hydrolysis by a specific enzyme that is on the post synaptic membrane or on the presynaptic membrane or is in the synaptic cleft Middle arrow diffusing out of the synaptic cleft Arrow pointing to left reuptake Active transport usually by Na dependent transporters re uptakes NT back into the presynaptic terminal Usually the transmitter is taken back up intact What s inside can add to the pool of transmitters Sometimes the NT can be degraded in the synaptic cleft and one or more of the hydrolysis products can be taken back up EX Neuromuscular junction NT acetylcholine In the synaptic cleft there is an esterase that hydrolyzes it into acetate and choline and that terminates the action of the transmitter Choline is reuptaken Responses of Postsynaptic cells Right NT binding to metabotropic protein We however will be focusing on ionotropic mechanisms on the left and middle Left NT binds to receptor which is an ion channel This is a receptor gated channel which opens What happens next Left hand side Na channel opens More Na in causing EPSP Excitatory brings membrane closer to threshold and consequently AP On right have ion channel that opens it is K or Cl K equilibrium potential is more negative than resting so if you open a K channel you will have hyperpolarization Opening a K channel will cause more K to go out than K coming in due to electrical gradient so you have net outwards movement of K which will hyperpolarize the cell In most cells Cl is distributed across the cell membrane such that its eq potential is more negative than resting If a cl channel opens you get outward Cl current which hyperpolarizes Outward current always hyperpolarize but since it is an anion have to keep in mind that an outward chloride current is carried by Cl ions moving in In either case hyperpolarization will result in inhibition making it less likely the postsynaptic cell will generate AP Chemical synapses can be INHIIBTED unlike electrical synapses Middle have a normally open channel NT binds to receptor and closes the channel Normally open channel can be closed when transmitter binds to it Cause less Na in causing IPSP Rods and cones in the retina do this Over on the right have ion channel closing was open before transmitter showed up now it is closed and there is reduction in outward K current of cell Myasthenia Gravis An understanding of synaptic function is important in treating addiction mental and neurological disorders Neuromuscular junction it is the excitatory synapse between spinal motor neurons and skeletal muscle
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