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55 Cards in this Set
- Front
- Back
Describe the function of the following proteins in NT release. Synapsin and CaMKII
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CAMKII mobilizes synaptic vesicles from the reserve pool by phosphorylating synapsin and thereby undoing the link that synapsin provides between synaptic vesicles and the restraining actin cytoskeleton
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Describe the function of the following proteins in NT release. Synaptotagmin
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A synaptic SNARE that contains binding sites for calcium. When it binds calcium, it enables the SNARE complex to twist in a way that forces fusion of the SV and plasma membrane bilipid layers, causing the release of transmitter.
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Describe the function of the following proteins in NT release. Synaptobrevin
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This snare, embedded in the membrane of the synaptic vesicle, binds to the PM snares, keeping the vesicle docked for NT release
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What is SNARE assembly regulated by?
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SNAPs and NSF (proteins
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What happens when toxins cleave the SNARE proteins?
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it blocks NT release because the SNARE protein does not bind Ca2+, still other molecules must be responsible for Ca2+ regulation of NT release.
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What is the importance of CAMKII?
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It binds to calmodulin in the presence of Ca2+ to stabilize the unfolded state which can phosphorylate substrates.
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During signal transduction, what happens to the receptor if there is no ligand?
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The receptor is off (α/β/γ are bound together in an inactive state with GDP in bound state)
-adenylate cyclase(makes cAMP) is also off. |
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During signal transduction what happens when ligand binds to receptor?
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Causes receptor to change conformation--> attracts α subunits of G protein--> α subunit exchanges GDP for GTP and dissociates from β/γ--> α subunit conformation and binds to adenylate cyclase, activating it--> adenylate cyclase turns ATP into cAMP (2nd messenger).
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How do you reverse the signal transduction pathway?
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1. α subunit cleaves GTP to GDP--> α subunit dissociates from adenylate cyclase, turning it off--> α binds to β/γ--> signal is off
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Why is there a need for 2nd messengers and G proteins?
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for amplification
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What does cAMP do?
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turns on kinase which causes glycogen phosphorylase to phosphorylate itself and become active, therefore, creating glucose.
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How do you reverse the signal from adrenaline?
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1. Alpha hydrolyzes GTP to GDP
2.Active receptor (ligand bound), is than inactive, the receptor becomes desensitized. 3. cAMP is degraded to 5' AMP by cAMP phosphodiesterase 4. cAMP activates PKA which phosphorylates target proteins, but protein phosphatase dephosphorylates protein and target proteins are converted back to original form. |
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What is the signal transduction for adrenaline?
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1. no ligand, G proteins and AC is off
2. Adrenaline (1st messenger, ligand) binds to B-adrenergic receptor. the receptor has affinity for alpha subunit, which causes it to exchange GDP for GTP. This causes alpha to leave B/y and leads to a conformational change 3.alpha-GTP activates AC and AC concerts ATP to cAMP 4.alpha cleaves GTP to GDP, which reverses the conformational change and alpha dissociates from AC. AC turns off and alpha associates with B/y |
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What does G stimulatory do?
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stimulates AC (cholera toxin changes the alpha subunit so that it is always bound to GTP
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What does phospholipase C do?
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PLC cleaves PIP2 into (DAG) and (IP3).
*PIP2 is a special rare phospholipid used for cell signaling. -DAG is hydrophobic so stays in PM -IP3 is hydrophilic so it is in the cytoplasm. |
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When IP3 binds what happens?
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it opens the channel, and Ca 2+ rushes out of the ER into cytoplasm.
-so before the signal [Ca2+]=10^-7 M and -after the signal [CA2+]=10^-5 M |
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What is the affect of the Ca 2+ released into the cytoplasm by IP3?
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Ca2+ activates Kinases.
1. 4 calcium binds to calmodulin, and creates a calcium/calmodulin complex 2. binds to calcium/calmodulin dependent protein kinase (CAM kinases) 3. phosphorylates specific target proteins and targets become activated or inactivated |
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What does DAG do?
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DAG acts to bind protein kinase c (PKC) to the membrane and activate its kinase activity. results in phosphorylation of specific targets.
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Describe the function of the following proteins in NT release. Syntaxin and SNAP-25
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Can form macromolecular complex that spans the two membranes, thus bringing them into close apposition. Such arrangement binds the snares of the synaptic vesicle, keeping it docked for NT release
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What does clathrin do and how does it work with dynamin?
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Clathrin is forcing the membrane to bend, dynamin causes it to pinch/cut off, and then binds to actin.
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What is the difference between Ionotropic and metabotropic receptors?
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1. Ionotropic NT receptors are ligand-gated ionic channels. They are made of transmembrane proteins that only allow specific ions to cross through the internal pore
2. Metabotropic NT receptors are G protein0coupled receptors that can activate downstream signaling. They amplify the signal, exert multiple different actions in response to activation, and offer specificity via compartmentalization of the downstream signaling machinery. |
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Suppose a presynaptic neuron were to fire, release glutamate, and elicit an EPSP at the same time as the PSP shown above. Further, suppose that, normally, the EPSP depolarizes the cell by 10 mV when acting alone. Would you expect the postsynaptic neuron to reach threshold when this EPSP is combined with the PSP above?
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No. One would expect perhaps a minor depolarization on top of the IPSP
shown above, but the magnitude of the additional depolarization due to the EPSP would not be 10 mV due to the countercurrent produced by the ions that are responsible for the IPSP. That is, this is not simple summation, rather the IPSP would in effect subtract from the depolarization elicited by the EPSP. The IPSP here is mediated by an outward flowing ICl- -> the exit of negative ions makes the inside of the cell a little more positive; how positive? only up to -50 – more positive than that and the Cl- will start flowing in again in order to keep the cell at it’s Eion. When glutamate is released at the same time, glutamatergic receptors allow Na+ to enter, but only a few channels are open. When the weak, inward INa+ tries to depolarize the cell (trying to reach its own ENa of +50), the ICl- will respond by driving Cl- inside the cell, making it more negative – an inward countercurrent. How could the excitatory current overcome the inhibitory current? The release of more glutamate would result in the opening of more Na+ channels, strengthening the INa until it is sufficient to overcome ICl- and reach threshold. |
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What happens when the NMJ is bathed in a solution that has low [Ca2+]?
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When the neuromuscular junction is bathed in a solution that has a low [Ca++], stimulating the motor neuron evokes EPPs whose amplitudes are reduced to about the size of MEPPs.
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What is the usual means of eliminating muscle contractions?
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is either to lower Ca++ concentration in the extracellular medium or to partially block the postsynaptic Ach receptors with the drug curare. Lowering the Ca++ concentration reduces NT secretion, thus reducing the magnitude of the EPP below the threshold for postsynaptic AP production and allowing it to be measured more precisely. As you see, stimulation of the motor neuron produces very small EPPS that fluctuate in amplitude from trial to trial.
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What is spatial summation?
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two action potentials from two different synapses add together.
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What is temporal summation?
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two action potentials that come right after one another from one neuron in a rapid succession. The two EPSPs adds together
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Define quantal release. What physical structure is thought to correspond to a quantum?
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In response to depolarization, NT’s are released into the synapse in multiples of
individual-unit fixed amounts of NTs. The smallest unit is one quantum of NTs. Individual synaptic vesicles each contain one quantum of NTs and are released in large quantities following depolarization --> 1 quantum per vesicle exocytosed yields quantal release of NTs. |
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What is LTP?
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Stands for long-term potentiation, meaning a long-lasting increase in the size of the EPSP
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How can you induce an LTP?
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You stimulate the presynaptic neuron 2 times in close succession with a tetanic stimulus of 100 Hz for the duration of 1 second each time
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What is meant by LTP being pathway-specific? Given this pathway-specific feature of LTP, how can heterosynaptic LTP be induced?
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It is the phenomenon where you get an LTP at a neighboring synapse can be explained by looking at the activity of that synapse. If the synapse is also being stimulated at the same time that we are inducing an LTP in another close synapse you will have an LTP at both synapses.
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Explain how NMDA receptors work and what they contribute to LTP.
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There are 3 conditions that need to be met for NDMA receptors to activate. Glutamate (agonist) and glycine (co-agonist) need to be present as well the Mg2+ block which is voltage-dependent has to be relieved. Once NMDA receptors activate, they let in Ca2+ to flow in to the postsynaptic cell and Ca2+ activates Protein Kinase C as well as Ca2+/Calmodulin kinase II and these two kinases activity leads to inserting more AMPA receptors into the postsynaptic membrane.
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What are the 3 advantages of IC second messenger signaling pathways?
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1. Molecular pathway from receptor to a target: provides access to the target (rather, say, than a wave of depolarization or an influx of calcium that unspecifically will affect anything voltage gated in the area)
2.Amplification: one molecule of glutamate can turn on several receptors, which will release, for example, a G protein, which can individually activate several kinases, which can stay on for a while and phosphorylate several targets 3. Compartmentalization: one can have signal transduction in one part of the cell, w/o turning on the rest of the cell; can keep the signaling pathways physically separate, for example, restricting effects to one single synapse while leaving the synapses of the rest of the cell alone) |
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Describe 4 sources of intracellular calcium, and 4 ways in which calcium is absorbed or removed from the cell.
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Sources of intracellular calcium: coltage gated calcium channels, ligand gated calcium channels, IP3 receptors on mitochondria, ryanodine receptors on mitochondria.
Calcium is removed or absorbed by: Na+/Ca2+ exchangers on cell membrane, Ca2+/H+ pumps on the cell membrane and mitochondria, Ca2+ binding buffer proteins, simple absorption by the mitochondria. |
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What happens when AMPA receptors are tetanically stimulated?
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Mg2+ blocking the NMDA receptor is removed. They provide a persistent depolarization that repels the Mg2+ and all Ca2= to flow through the NMDA receptors and cause intracellular changes below.
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True or False, second time you stimulate the presynaptic membrane, you get a bigger second PSP due to the piling up of calcium.
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True, this causes a higher probability of vesicles coming out.
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What happens when their is a big interval between the pulses (post-tetanic potentiation)?
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The bigger the interval between the pulses the more calcium cleared out and the less the facilitation. Depends on how quickly the terminal can get rid of the previous calcium.
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One form of short-term synaptic plasticity involves that of normal calcium. What happens?
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Normal calcium leads to a tetanus which causes a strong and fast depression because of the use up of the vesicle pool faster than you can use it and when you release it it goes back to normal
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What happens if you decrease the calcium concentration for short-term synaptic plasticity?
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If you really decrease the [Ca2+] you keep getting a release of vesicles and neurotransmitter, but you don't get that depression because even though you're firing very fast, you never sufficiently deplete those release sites.
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What happens when you release fewer vesicles?
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The fewer vesicles that you release from the presynaptic terminal, the less the depression
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LTP's are pathway specific so if tetanus occurs in one synapse and not in the other, what will happen?
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Tetanus in one synapse will result in LTP only at that synapse, not all the synapses in the area (even the ones that are really close by). So if pathway 1 is tetanized and gets stimulated and stays up there for about an hour, but pathway 2 never got anything, stays always about the same.
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What does state-dependent mean?
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pairing of pre and post synaptic events which must have postsynaptic depolarization while stimulating the EPSP. If the schaffer collateral fired but it wasn't strong enough to depolarize the membrane, no LTP.
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What is the role of calcium in molecular mechanisms of LTP?
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Ca2+ is needed in the postsynaptic cell. Put Ca2+ chelater BAPTA (a very good chelator of calcium) and it will block LTP formation.
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When NMDA receptors are blocked with APV then no LTP occurs. How does it affect AMPA's or GABA?
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Doesn't block AMPA's or GABA or other; quite specific
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What are the three conditions for activation of NMDA receptors?
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1. Glutamate
2. Glycine (co-agonist) 3. Relieve the magnesium block; voltage dependent. |
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What is the postsynaptic mechanism of LTP?
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1. Ca2+ entry activates postsynaptic CaMKII and PKC
2. recruit intracellular AMPA receptors which move to surface at postsynaptic sites |
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What is the role of Mg2+ in regards to NMDA receptors?
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Mg2+ blocks NMDA receptors. It is removed when AMPA receptors are tetanically stimulated they provide a persistent depolarization that repels the Mg2+ and allows calcium to flow through the NMDA receptors and cause intracellular changes below.
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Name three major categories of receptors and provide an example of each, explaining which feature is characteristic of each class
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-Surface receptors activated by CELL IMPERMEANT AGONISTS: Examples include ligandgated ion channels, G protein-coupled receptors, and enzyme-linked receptors (receptor protein kinases), all of which have EXTRACELLULAR surface BINDING SITES for specific ligands. NOTE: enzyme-linked receptors have external binding sites but INTERNALLY-bound enzymes
(kinases) -Surface receptors activated by CELL ATTACHED (OR TRANSMEMBRANE) AGONISTS: These receptors activate only in close proximity (or direct contact) with adjacent cells. Examples include EPHRIN, integrins, and NCAMS. -Intracellular receptors activated by CELL PERMEANT AGONISTS: Examples include numerous hydrophobic molecules such as steroid and thyroid hormones, which have the ability to freely diffuse through the plasma membrane and bind to intracellular targets |
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What are the 3 main purposes of signal transduction?
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i) to provide a molecular pathway from receptor to target
ii) amplification: to increase the molecular response possibly by orders of magnitude Starting Material Acetyl CoA + Choline Glutamine Glutamate Enzyme Responsible for synthesis Choline acetyltransferase Glutaminase Glutamic acid decarboxylase Neurotransmitter Acetylcholine Glutamate GABA Vesicle Pump VAChT VGLUT VGAT Enzyme Responsible for break down acetylcholinesterase Glutamine synthase None. Recycled as GABA iii) compartmentalization: to separate downstream signals and allow them to exert specific influences in various locations |
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Indicate the three most common categories (examples) of second messengers
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i) Ca++
ii) cyclic nucleotides (such as cAMP) iii) diacylglycerol (& IP3) |
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What is LTP?
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Stands for long-term potentiation, meaning a long-lasting increase in the size of the EPSP.
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How can you induce an LTP?
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You stimulate the presynaptic neuron (e.g. the CA3) 2 times in close succession with a tetanic stimulus of 100 Hz for the duration of 1 second each time
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Define PSD95.
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a scaffold protein that crosslinks and anchors various players (receptors, second messengers) that are desired at the postsynaptic membrane
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Define “calcium bottle”
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The calcium that enters a dendritic spine will stay sequestered at that spine, although the current
may be able to leave and affect other synapses. (the result is a high, local concentration at a very specific compartment) This can be visualized through calcium fluors that light up in the presence of calcium. |
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List 4 functions of glia that demonstrate their involvement in neuronal signaling. Which type of glia does this?
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Glial Astrocytes perform the following:
Recycle NTs Receive synaptic input Release NTs (ex. glutamate) Release “synaptogenic components,” compounds that are used in generating synapses |
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(a) What compound can be produced from arginine that can exert retrograde signaling at synapses? How can it do this, i.e. what unique physical feature does the component have and how does that help? (b) Name another class of retrograde signaling compounds at synapses.
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a) NO synthase converts Arginine into citrulline and the transmitter, Nitric oxide (NO), which is unique because it occurs in the gaseous phase and can diffuse out of the cell through the plasma membrane, as illustrated in Figure 6.2.
b) Endocannabinoids |