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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.

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Step 1 - Action potential arrives at the terminal end of the presynaptic cell.

Step 3 - Acetylcholine is released. Move the synaptic vesicle to the terminal end of the neuron. SNAP/SNARE proteins interact to bring the vesicle in position to fuse with the cell membrane.

Step 2 - Calcium channels open in the 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 4 - Acetylcholine binds to postsynaptic receptors. Acetylcholine traverses the synaptic cleft to bind to the acetylcholine receptor on the postsynaptic membrane

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3b. Identify the ion that triggers the SNAP/SNARE proteins to cause the synaptic vesicle to “kiss

and run”. 3c. What molecule is released into the synaptic cleft in this model? 3d. Why is it important that acetylcholinesterase is present in the synaptic cleft? 3e. What type of channel is the acetylcholine receptor in the post synaptic cell?

Step 5 - Ion channels open in the postsynaptic membrane. The acetylcholine receptor opens to allow sodium ions to follow their concentration gradient into the postsynaptic cell. Depolarization of the postsynaptic cell occurs and an action potential may be generated in the post synaptic cell.

Step 6 - Termination of acetylcholine effects. The enzyme acetylcholinesterase breaks the neurotransmitter down into acetic acid and choline. An uptake receptor transports choline back into the presynaptic cell for use in the synthesis of more acetylcholine in the presynaptic cell.

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3f. What happens in the post synaptic cell when acetylcholine binds to the receptor? 3g. Identify the cholinergic synapse modeled excitatory or inhibitory. Explain your choice. 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. 4b. How does sarin perturb the cholinergic synapse?

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4c. Compare the chemical structures of nicotine, sarin and acetylcholine. How might Aricept perturb the cholinergic synapse?

4d. Imagine where other perturbances might occur in the synapse. Record your thoughts.

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.

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Step 2 - Calcium channels open in the 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 1 - Action potential arrives at the terminal end of the presynaptic cell.

Step 4 - Dopamine traverses the synaptic cleft to bind to the extracellular domain of the metabotropic receptor in the postsynaptic membrane. The intracellular domain of the metabotropic receptor binds to G-proteins. The G-protein has three subunits: alpha(α), beta(β), and gamma(γ).

Step 3 - Dopamime is released. Move the synaptic vesicle to the terminal end of the neuron. SNAP/SNARE proteins interact to bring the vesicle in position to fuse with the cell membrane.

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5b. What neurotransmitter is released into the synaptic cleft in this model? 5c. Identify the dopaminergic synapse modeled as excitatory or inhibitory. Explain your choice. 5d. Describe how an ionotropic receptor differs from a metabotropic receptor.

Step 6 - The effects of dopamine are terminated when dopamine is removed from the synaptic cleft by the dopamine uptake transporter and returned to the vesicle.

Step 5 - Bound dopamine activates the metabotropic receptor. The α subunit dissociates from the βγ complex. The α subunit triggers a signal cascade that ends in the opening of ion channels, depolarizing the postsynaptic cell.

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5e. Do ions move through this metabotropic receptor? 5f. Identify the subunits of the G-protein. 5g. Which of these subunits activates adenylyl cyclase? 5h. What is the role of adenylyl cyclase in this signal cascade? 5i. What is the role of protein kinase in this model of neurotransmission?

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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? 6b. What long term effect might repeated exposure to cocaine have on the dopaminergic

synapse?