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Part III: Modeling Neurotransmission – a Cholinergic Synapse

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Part III: Modeling Neurotransmission – a Cholinergic Synapse Part III: Modeling Neurotransmission – A Cholinergic Synapse Operation of the nervous system is dependent on the flow of information through chains of neurons functionally connected by synapses. The neuron conducting impulses toward the synapse is the presynaptic neuron, and the neuron transmitting the signal away from the synapse is the postsynaptic neuron. Chemical synapses are specialized for release and reception of chemical neurotransmitters. For the most part, neurotransmitter receptors in the membrane of the postsynaptic cell are either 1.) channel-linked receptors, which mediate fast synaptic transmission, or 2.) G protein-linked receptors, which oversee slow synaptic responses. Channel-linked receptors are ligand-gated ion channels that interact directly with a neurotransmitter and are called ionotropic receptors. Alternatively, metabotropic receptors do not have a channel that opens or closes but rather, are linked to a G-protein. Once the neurotransmitter binds to the metabotropic receptor, the receptor activates the G-protein which, in turn, goes on to activate another molecule. 3a. Model the ionotropic cholinergic synapse shown below. Be sure to label all of the following: voltage-gated sodium channel, voltage-gated potassium channel, neurotransmitter, synaptic vesicle, presynaptic cell, postsynaptic cell, potassium leak channel, sodium-potassium pump, synaptic cleft, acetylcholine receptor, acetylcholinesterase, calcium channel. When a nerve impulse (action potential) reaches the axon terminal, it sets into motion a chain of events that triggers the release of neurotransmitter. You will next model the events of neurotransmission at a cholinergic synapse. Cholinergic synapses utilize acetylcholine as the chemical of neurotransmission. MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 1 Step 1 - Action potential arrives at the Step 2 - Calcium channels open in the terminal end of the presynaptic cell. presynaptic axon terminal. Open the calcium channels (red) and move some calcium ions to the interior of the neuron. Calcium ions bind to synaptotagmin. - Acetylcholine binds to Step 3 - Acetylcholine is released. Move the Step 4 synaptic vesicle to the terminal end of the neuron. postsynaptic receptors. Acetylcholine SNAP/SNARE proteins interact to bring the vesicle traverses the synaptic cleft to bind to in position to fuse with the cell membrane. the acetylcholine receptor on the postsynaptic membrane MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 2 Step 5 - Ion channels open in the Step 6 - Termination of acetylcholine postsynaptic membrane. The effects. The enzyme acetylcholinesterase acetylcholine receptor opens to allow breaks the neurotransmitter down into sodium ions to follow their concentration acetic acid and choline. An uptake receptor gradient into the postsynaptic cell. transports choline back into the presynaptic Depolarization of the postsynaptic cell cell for use in the synthesis of more occurs and an action potential may be acetylcholine in the presynaptic cell. generated in the post synaptic cell. 3b. Identify the ion that triggers the SNAP/SNARE proteins to cause the synaptic vesicle to “kiss and run”. (Ca2+) 3c. What molecule is released into the synaptic cleft in this model? (acetylcholine) 3d. Why is it important that acetylcholinesterase is present in the synaptic cleft? (Acetylcholinesterase removes acetylcholine from the synaptic cleft in order to terminate nervous transmission.) 3e. What type of channel is the acetylcholine receptor in the post synaptic cell? (a ligand-gated sodium channel) MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 3 3f. What happens in the post synaptic cell when acetylcholine binds to the receptor? (Sodium ions enter through the acetycholine receptor in the post synaptic cell resulting in a depolarization of the cell.) 3g. Identify the cholinergic synapse modeled excitatory or inhibitory. Explain your choice. (The cholinergic synapse is excitatory because it results in a depolarization of the postsynaptic cell.) Part IV: Modeling a Perturbance in a Cholinergic Synapse Next you will introduce two substances that perturb neural transmission in the cholinergic synapse. Nicotine binds to the acetylcholine receptor to open the channel. Sarin binds to acetylcholinesterase. Model where these substances bind in your synapse. 4a. How would nicotine affect nervous transmission in this synapse. (The acetylcholine channel would be held open allowing an influx of sodium ions, depolarizing the cell.) 4b. How does sarin perturb the cholinergic synapse? (Acetylcholine will not be able to be removed from the synaptic cleft.) MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 4 4c. Compare the chemical structures of nicotine, sarin and acetylcholine. How might Aricept perturb the cholinergic synapse? (Aricept binds to acetylcholinesterase preventing the breakdown of acetylcholine.) 4d. Imagine where other perturbances might occur in the synapse. Record your thoughts. (various) Part V: Modeling Neurotransmission – A Dopaminergic Synapse 5a. Model the metabotropic dopaminergic synapse shown below. Be sure to label all of the following: voltage-gated sodium channel, voltage-gated potassium channel, dopamine, synaptic vesicle, presynaptic cell, postsynaptic cell, potassium leak channel, sodium- potassium pump, synaptic cleft, G-protein coupled receptor, calcium channel, dopamine transporter, and vesicular transporter When a nerve impulse (action potential) reaches the axon terminal, it sets into motion a chain of events that triggers the release of neurotransmitter. You will next model the events of neurotransmission at a dopaminergic synapse. MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 5 Step 1 - Action potential arrives at the Step 2 - Calcium channels open in the terminal end of the presynaptic cell. presynaptic axon terminal. Open the calcium channels (red) and move some calcium ions to the interior of the neuron. Calcium ions bind to synaptotagmin. Step 3 - Dopamime is released. Move the Step 4 - Dopamine traverses the synaptic synaptic vesicle to the terminal end of the cleft to bind to the extracellular domain of neuron. SNAP/SNARE proteins interact to the metabotropic receptor in the bring the vesicle in position to fuse with the postsynaptic membrane. The intracellular cell membrane. domain of the metabotropic receptor binds to G-proteins. The G-protein has three subunits: alpha(α), beta(β), and gamma(γ). MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 6 Step 5 - Bound dopamine activates the Step 6 - The effects of dopamine are metabotropic receptor. The α subunit terminated when dopamine is removed from dissociates from the βγ complex. The α the synaptic cleft by the dopamine uptake subunit triggers a signal cascade that transporter and returned to the vesicle. ends in the opening of ion channels, depolarizing the postsynaptic cell. 5b. What neurotransmitter is released into the synaptic cleft in this model? (dopamine) 5c. Identify the dopaminergic synapse modeled as excitatory or inhibitory. Explain your choice. (The dopaminergic synapse modeled is an excitatory metabotropic synapse. The postsynaptic cell is depolarized setting up an action potential.) 5d. Describe how an ionotropic receptor differs from a metabotropic receptor. (The acetylcholine receptor is an ionotropic receptor in that when the neurotransmitter binds to the receptor, a channel opens allowing ions to traverse the membrane. The dopamine receptor is a metabotropic receptor in that the eventual movement of ions through a channel depends on one or more metabolic steps.) MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 7 5e. Do ions move through this metabotropic receptor? (no) 5f. Identify the subunits of the G-protein. (alpha, beta and gamma subunits) 5g. Which of these subunits activates adenylyl cyclase? (alpha) 5h. What is the role of adenylyl cyclase in this signal cascade? (Adenylyl cyclase converts ATP to cyclic AMP which in turns binds to the regulatory domain of protein kinase.) 5i. What is the role of protein kinase in this model of neurotransmission? (Protein kinase eventually phorphorylates an ion channel allowing ions to flow through the membrane depolarizing the neuron.) MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 8 Part VI: Modeling a Perturbance in a Dopaminergic Synapse Next you will introduce a substance that perturbs neural transmission in the dopaminergic synapse. Cocaine binds to the dopamine reuptake protein in the presynaptic cell. 6a. How would cocaine affect nervous transmission in this synapse? (Cocaine prevents the reuptake of dopamine by the dopamine reuptake receptor resulting in a buildup of dopamine in the synapse.) 6b. What long term effect might repeated exposure to cocaine have on the dopaminergic synapse? (The brain starts to adapt and becomes less sensitive to natural reinforcers and to the drug inteself. Tolerance may develop meaning that higher doses and/or more frequent use of cocaine is needed to register the same level of pleasure experienced during the initial use.) MSOE Center for BioMolecular Modeling Synapse Kit: Section 3-6 | 9 .
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