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USC BISC 307L - Synaptic Transmission (continued)
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BISC 307L 2nd Edition Lecture 8Current LectureSteps in Chemical Synaptic Transmission5 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 theneurotransmitter.Release occurswhen actionpotential comesdown the axonand invades theterminal. NeurotransmitterreleaseThe action potentials arecoming downwards. Dothey 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. Vesiclecomes off, retaining its integrity.Back to the steps-4. 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 2nd 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 cellsRight = 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 GravisAn understanding of synaptic


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