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00:00 | Recording. So today is lecture four cellular neuroscience. We're going to continue |
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00:07 | about glutamate. Ergic signaling. We off talking about an M. |
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00:13 | A. Ample and keen eight receptors are pictured here and we said that |
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00:22 | which is a neurotransmitter which our brain make its endogenous. It's an endogenous |
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00:32 | . Endogenous means it's produced inside the agonist. That means it's going to |
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00:37 | these receptors all three of them and three of these receptors also have their |
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00:44 | distinct chemical agonists and those are chemical which are basically exogenous chemicals. Ampara |
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00:58 | chemicals and M. D. And kind eight. And because originally |
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01:04 | same glutamate would activate all three receptors was no way to distinguish them |
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01:11 | It's a very clear way to distinguish because they have their own specific agonists |
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01:20 | empire is not going to bind an . D. A. And an |
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01:24 | . D. A. Is not to buy into an amp and so |
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01:28 | . So we're gonna get in more and agonists and antagonists and a little |
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01:33 | more of this terminology. So the difference between am Paquin aid or what |
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01:41 | call non NMDA receptors is that once is released pre synaptic aly the binding |
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01:47 | glutamate an empire and kinda receptors will for deep polarization and the flocks of |
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01:54 | inside and later for the influx of from inside to outside in the |
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02:02 | And apple receptor is going to be for the initial phase of the |
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02:10 | P. S. B. So we look at glutamate release at this |
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02:18 | here and we are recording from a here And this is the trace from |
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02:27 | neuron here. We're recording activity is to be a deep polarization. So |
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02:33 | talked about resting membrane potential let's say syllables and this can go to let's |
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02:39 | -15 syllables. There's going to be deep polarization which is excitatory, post |
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02:48 | potential. Excitatory p poss synaptic posson optic potential. And the early |
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02:59 | phase of this E. P. . P. Is because of the |
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03:03 | A receptor. And the reason why because as soon as glutamate is released |
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03:10 | binds to a receptor that is going be influence of sodium. This later |
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03:17 | of E. P. S. . Is mediated by N. |
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03:21 | D. A receptors. And the for it is first of all, |
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03:32 | M. D. A receptors have binding site for glutamate. It has |
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03:38 | binding site for glycerine as a co and inside of the channel and has |
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03:45 | binding side from magnesium and magnesium is this channel. And in order for |
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03:55 | block to be relieved there has to a deep polarization that happens initially through |
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04:04 | amper receptors. So emperor receptors first the initial D polarization and that allows |
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04:11 | the magnesium to get kicked out of M. D. A receptor opens |
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04:16 | M. D. A receptor and . D. A receptor is responsible |
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04:19 | the late portion of the E. . S. P. So a |
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04:25 | of things here that receptors they will about 20 PICO cements of current and |
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04:36 | M. D. A Will conduct Pecos emails of current. So the |
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04:44 | it's a larger poor and more islands flux through that poor in the end |
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04:50 | M. D. A receptor essentially more to the post synaptic deep |
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04:56 | But it takes time to wake it because each one of these receptors we |
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05:06 | about has their own agonists ampara and . D. A. Kind |
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05:11 | They also have their own distinct So ALpa is going to get blocked |
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05:19 | kind Nate are both going to get by a substance called C. |
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05:24 | Q. X. And an D. A receptor is going to |
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05:30 | blocked by a substance called A V. Or 85. So blockers |
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05:39 | antagonists sometimes can be used interchangeably antagonists will also either diminish or block or |
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05:50 | of certain receptor channels. Because an . D. A receptor has to |
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05:58 | the pre synaptic neurotransmitter release and binding glutamate and because it has to sense |
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06:05 | post synaptic deep polarization for this magnesium leave the channel, it is referred |
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06:11 | as coincidence detector. We say that has slow kinetics because it's responsible for |
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06:21 | late portion of the PSP. So fast kinetics and the initial activation and |
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06:27 | D. Polarization is through the ampara an M. D. A receptor |
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06:33 | sample keen and the late portion as an N. D. A. |
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06:39 | some uh glutamate receptors. Meadow below , ample canaanite and N. |
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06:50 | D. A receptors are ion a . Their eye on a tropic because |
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06:57 | binding chemical glutamate binding to this receptor open the actual channel poor and allow |
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07:06 | the flux of ions. That's why ion a tropic and then all of |
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07:12 | M. D. A receptors, going to be the flocks of sodium |
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07:19 | and calcium for ample only some of ample receptors will allow for the flocks |
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07:26 | cows. So the eye on a nature of these channels and what ions |
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07:33 | through these channels is also different and entering inside the south is not contributing |
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07:41 | much to the charge as much as may contribute to synaptic transmission and it |
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07:49 | contribute to the cellular processes calcium two ion can act as a secondary messenger |
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07:58 | the cells to. Now this receptors here are metabolic tropic glutamate receptors and |
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08:08 | this case glutamate will have a binding of these on these receptors. But |
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08:14 | of opening a channel or on this to which it binds it is now |
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08:22 | to cause a downstream cellular reaction by g protein complexes and this g protein |
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08:33 | once they get activated and these subunits catalyzed they can cause activation of other |
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08:41 | messengers enzymes in many different functions inside cell including altering the transcription factors. |
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08:54 | is what we call the basic mode operation of G proteins. So if |
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09:03 | can see that G protein coupled receptor you have this jew protein which is |
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09:10 | either associated or bound to the G coupled receptor and you have a transmitter |
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09:18 | binds to this receptor and B. doesn't open the channel for poor but |
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09:25 | it activates the alpha subunit of this protium and this alpha subunit and beta |
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09:38 | subunits. They disassociate one from Alpha. Now can target This effect |
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09:47 | protein one and can stimulate this effective and beta gamma subunit, the other |
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09:58 | of it can also influence the effect proteins nearby by binding to them. |
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10:07 | a lot of these proteins, maybe associated proteins. This is the basic |
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10:14 | of operation. Is that ligand never and to the cell of course ions |
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10:21 | flux through the receptor. But alpha this catalytic activation of these subunits is |
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10:35 | in changing ion flux is through nearby or changing intracellular signaling in general. |
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10:47 | , so in your class documents and blackboard you have lecture reading and supporting |
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11:00 | . For example, when we talked the hippocampal circuit, there is information |
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11:08 | that article and the figure that we when I uh we were discussing fragile |
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11:16 | syndrome and spines and I pointed to article, this is the link to |
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11:25 | article, fragile X. The following that you're seeing here. Not this |
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11:31 | but this one it's actually from this which is glutamate ergic mechanisms related to |
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11:47 | . We'll review this in a second . I've uploaded a description of uh |
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11:59 | basically an M. D. Receptor physiology from Quillen College of Medicine |
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12:09 | in Cleveland clinic. So what are of the things that are important that |
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12:16 | noted here about an M. A receptor the prime or excited to |
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12:22 | in the human brain glutamine. It integral role in synoptic elasticity. Why |
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12:35 | M. D. A receptor is positioned to bind the activity from pre |
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12:41 | and Tosin optic sells because it has recognize pre synaptic cellular neurotransmitter. It |
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12:48 | to have passed synaptic deep polarization. it has to have basically there's two |
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12:57 | and and because of that it's at at the crew of the synaptic |
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13:08 | Now it says its synaptic plasticity is to be the basis of memoir information |
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13:13 | FDA receptors are very important here. if plasticity is a cellular mechanism to |
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13:24 | and memory that means N. D. A function which is crucial |
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13:28 | plasticity is crucial to learning and The other thing that's noted here and |
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13:36 | . D. A. Receptors appear have involvement in a process called excite |
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13:40 | toxicity excited toxicity may play a role the path of physiology of variety of |
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13:48 | such as epilepsy or Alzheimer's disease. what is excited toxicity If an |
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13:56 | D. A receptor function is the flux of calcium inside the cells |
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14:04 | cause what is called calcium exciter And too much calcium inside the south |
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14:11 | actually turn on mechanisms that can eventually lead to apoptosis and neuro degeneration if |
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14:18 | is uncontrolled calcium levels. So now have excited toxicity. This excited toxic |
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14:25 | and an M. D. A function here is very important tight control |
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14:30 | opening and closing of an M. . A receptor. The flux of |
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14:33 | inside the cell. Many drugs inhibit M. D. A receptor including |
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14:40 | and Tensai claudine to common drugs of but also ketamine is there is not |
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14:52 | drugs of abuse. They also are drugs as well. Yes so let |
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15:01 | like in India receptors like the excitable would be like tetanus type stuff. |
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15:09 | Except that in the brain you would that a seizure. Yes precisely. |
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15:15 | much of glutamate. Too much of tampon and controlled an M. |
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15:20 | A. Activity can lead to abnormal and yeah a similar similar physiology will |
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15:28 | into that a little bit later in course similar physiology etc. And muscular |
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15:33 | but in the brain it would be synchrony in seizures. So yeah well |
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15:41 | this is introduction cellular of course we discussed that glutamate Nate. They're all |
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15:53 | a tropic? It has subunits and or two and 3. Okay and |
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16:06 | has extra cellular ligand binding domain and trans membrane ion channel when ligand binds |
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16:13 | M. D. A receptor ligand domain closes like a clam shell. |
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16:20 | closure leads the opening of the trans . Our ion channel come back to |
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16:24 | in a second and M. A receptor. You can read this |
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16:32 | . All of these things that we here are kind of a reviewed in |
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16:36 | detail and this is a really good read of about three pages and we're |
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16:43 | going to go through everything here. we already did. We talked about |
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16:49 | detector for example calcium serves a secondary . It's important for development of the |
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17:03 | myriad of functions with central nervous So it has a lot of functions |
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17:09 | is involved in a variety of disease including Alzheimer's huntington's epilepsy stroke, major |
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17:15 | , tinnitus, which is ringing in air's anti NMDA receptor, encephalitis, |
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17:21 | metal poisoning, migraines. Mhm aside significance and M. D. Receptors |
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17:29 | pharmacological target of both therapeutic drugs and abuse. So ketamine, an MD |
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17:38 | sedative and aesthetic off label as an or recreational is hallucinogenic drug of abuse |
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17:45 | there's actually anti depression treatments with with ketamine to ethanol. Common recreational target |
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17:56 | is um M. D receptors through mechanisms. It's just find this common |
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18:02 | drug it's served on campus. So a lot of a lot of |
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18:11 | Okay so you'll say my my my do I need to know all of |
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18:15 | stuff the details the disorders and stuff that. No. All of the |
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18:21 | that we've so far discussed in this this page here. Introduction and cellular |
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18:27 | are the things that I'd like for to be responsible for in the first |
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18:31 | and as far as the knowing what it's involved in, we actually going |
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18:36 | go into that a little bit But the fact that it does seem |
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18:41 | be important for learning and memory, does seem to be really important for |
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18:44 | side a toxicity from which you can seizures in epilepsy and a slew of |
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18:48 | neurological disorders then that that is important know for for our purposes. |
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18:58 | the other thing that I had on in this slide actually is that there |
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19:05 | PCP hallucinations, schizophrenia. MK What that illustrates is that each one |
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19:13 | these receptors will have multiple binding sites different substances. Some of our natural |
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19:21 | endogenous others are natural exogenous agonists and , others are chemicals that are |
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19:30 | illicit drugs and things like that. what is important is for us to |
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19:37 | looking a little bit broader to glutamate and how does the world interpret glutamate |
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19:45 | ? This is a good review that like to use. And let's start |
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19:52 | that. So, first of all said there is ample receptors and then |
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19:57 | who who keeps track of all of subunits. So there's actually these bodies |
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20:03 | union basically clinical pharmacology and then they another regulatory and standardization bodies actually have |
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20:13 | keep track of these things. And today we're gonna be looking at glue |
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20:17 | two receptor structure which is ample receptor . But all of this norman |
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20:26 | if you look at these blue to cake, blue cake, green, |
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20:31 | , green blue and there's a slight between naming and two non monocultures Hugo's |
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20:41 | gene based but in short you still ample N N. M. |
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20:48 | A receptor families. There's a glutamate receptor that we don't mention and talk |
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20:54 | about this course. Alright, so look at this what is illustrated here |
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21:00 | is in our notes. So first all the structure we have sub units |
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21:05 | each one of these subunits in this we're looking at the glue A two |
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21:11 | is ample receptor is comprised of these membrane M 34 and this inter membrane |
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21:21 | em to having them basically four trance slash numbering and started components. There |
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21:34 | the H two and terminus nitrogenous terminus is on the outside it's extra |
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21:45 | Then there is C. 00. terminus which is intracellular the S. |
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21:57 | . Agonist binding residues. So you S one In Orange & S. |
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22:06 | in Turquoise. Is this nice purple here called flip flop. So it's |
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22:19 | it's a region that has either flip the flopped structural configuration in the ample |
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22:26 | and that distinguishes similar ample receptors structural functional. So in the previous paper |
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22:37 | said that when the agonist binds to receptor the clamshell closes and this illustrates |
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22:47 | B now kind molecule which is binding . It will also activate ample receptors |
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22:56 | binding here between the S. One S. Two regions. So now |
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23:02 | looking from the top here. One. There's two regions here, |
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23:07 | flip flop flop region here. And then it says here this is |
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23:16 | kindness stagnant molecules black with a deep of the protein the two disqualified bonded |
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23:23 | and yellow. This is what we the bag bone, the representation of |
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23:30 | going on and where this kind of is found and so when kinda binds |
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23:37 | the side between S. One and . Two, this clam shell kind |
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23:45 | a comes from closes together. So lot of the agonists may be partial |
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23:55 | , you will hear that antagonists are or the full agonists. What makes |
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24:02 | full agonist is more of that clam closer you would see there the more |
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24:10 | the structural conformational change the receptor undergoes is likely going to open it more |
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24:17 | or have it open for a longer . As an agonist partial means that |
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24:25 | may bind to a side but it cause a partial closure of this clamshell |
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24:33 | may not be as effective at opening receptor channel for here in the sample |
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24:44 | . This is a a figure that actually in your lecture notes also. |
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24:52 | this is the next figure that discusses antagonist modulators. So let's talk about |
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25:02 | again by looking at the actual Well, screaming. Okay, so |
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25:23 | because I think it's better resolution. you have this amp kinase receptors and |
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25:30 | have first of all major domains binding for agonists, antagonists and modulators in |
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25:38 | ligand binding domain which is L. . D. This orange domain, |
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25:45 | . B. D. Amino terminal . Right. We just looked at |
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25:51 | amino terminus, the Mh two domain is A. T. D. |
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25:55 | the extra cellular side of the of receptor protein and the trans membrane dough |
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26:04 | , T. M. D. green. The receptor targets of Ligon |
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26:12 | for one or several subunits are listed parenthesis and kind and indicates that the |
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26:18 | selectively selectively targets glue A or glue receptor subunits respectively. Okay, let's |
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26:24 | at this. So look at There's different substances basically will bind to |
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26:34 | portions. So a single receptor is a door that has like 20 potential |
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26:43 | and each one of these locks will for that door to either open partially |
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26:51 | a lot open halfway, stay open a long time once its open or |
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26:56 | in the case of antagonists keep it . Does't matter what happens. So |
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27:03 | the point. I'm not going to you to tell the difference where there |
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27:10 | uh an era system of cyclo thighs versus and uh zinc or magnesium binding |
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27:22 | . But the point is to illustrate multiple binding sides. And the second |
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27:29 | here is to talk about agonists agonists the molecules that are going to open |
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27:38 | this case the receptor channel. But if they're acting through metabolic tropic receptors |
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27:46 | going to basically cause the Cathal Asus that G protein once it binds to |
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27:51 | receptor target. So that's an agonist antagonist is something that is going to |
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28:00 | or cause a closure the third The same as you. You can |
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28:06 | a partial versus full agonists. You also have partial versus full antagonists. |
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28:22 | . Now there is another term that didn't try down here but I would |
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28:27 | for you to know it's called competitive and competitive antagonist is an antagonist but |
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28:42 | competing with the agonist for the same site. So a lot of times |
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28:51 | and antagonists they will have their own binding sites on this three dimensional structure |
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29:00 | target a different sequence of amino But if it's a competitive antagonist that |
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29:06 | it's going to compete for the site agonists are supposed to activate the receptor |
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29:17 | and it's not going to allow for receptor channel to be activated. So |
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29:23 | a competitive antagonist is competing with the and it's not allowing for the agonist |
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29:30 | buy into that receptor basically like and . Mm enzyme inhibitors versus maybe they |
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29:50 | probably yeah absolutely would have similar substances compete for for inhibiting their function versus |
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29:59 | their function and there's probably similar So in this case because we're talking |
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30:07 | endogenous exogenous pharmacological drugs that will be all of these different sides and |
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30:15 | D. A. Receptor involved in and memory involved in all of these |
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30:19 | disorders having a variety of all of binding sites as it's discussed in one |
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30:25 | your taxes a huge target for drug . So because there's so many different |
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30:35 | in so many different ways you can and the significance of the actual target |
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30:40 | this case an M. D. receptor is pharmacological target. Okay so |
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30:51 | there are also Alice Terek modulators. so when we talk about modulators we |
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30:59 | about Alice Terek modulated which means that will have and they can be Alice |
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31:06 | agonists and they can be al hysteric Which bio hysteric means that they will |
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31:16 | a different binding site. There's still 02 molecules can activate that receptor uh |
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31:28 | the same with an antagonist. So molecules can block or inhibit the function |
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31:34 | that receptor but they will do it binding in two different sites. They're |
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31:39 | competing for the same sides. They're a replica of each other. They |
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31:43 | have two different ways of approaching that . So a lot of times actually |
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31:53 | uh talk about Alice Terek modulators if and antagonist and sometimes maybe a better |
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32:02 | is a negative Alistair IQ modulator versus positive Alistair IQ modulator. Because you |
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32:10 | think of negative Alistair IQ modulators, that will impact the function of whatever |
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32:16 | being activated, antagonized uh in an function. And a positive Alistair IQ |
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32:25 | would be like a booster but it be a booster to both agonist to |
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32:30 | on function or two antagonists to boost function. So the better way of |
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32:35 | about uh hysteric modulators. His negative hysteric versus positive al hysterics because they |
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32:42 | affect the functions of both the agonists antagonists. Okay, so we're going |
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33:00 | skip a lot of information on this and then again in this particular tax |
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33:06 | would just invite you to look through figures, the figure legends and maybe |
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33:13 | associated text in those pages to those . And of course, by all |
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33:19 | , if you're interested in in general the whole article, it's it's it's |
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33:26 | that long. It's only both pages so. And it's a overview introductory |
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33:33 | . It comes from the jaspers mechanisms epilepsy sees a lot of what we |
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33:42 | about excitation and inhibition a lot of functional information about what cells do came |
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33:51 | from research and epilepsy and seizures because is such a cell activity disorder that |
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34:00 | can record and analyze that allowed us understand the how different cells function, |
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34:07 | they communicate with each other, how are involved. And so when we |
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34:14 | about Glee um we talk about tripartite , we're gonna come back a little |
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34:19 | and talk about glee in here Now is in particular potential mechanisms by which |
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34:26 | could boost astra acidic glutamate release. this is a scheme here and while |
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34:36 | talking about it here because glutamate Clarence part and synthesis the amount of glutamate |
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34:42 | is available to neurons is regulated by and ostracized in particular. So we |
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34:50 | control of a specific limit released by protein coupled receptors. It's glutamate which |
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34:59 | acting on measurable tropics. So this em just like we learned about |
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35:06 | A subsequent K. V. The stands for voltage here I am and |
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35:15 | small case and blue are five and . Stands for metal but tropic glutamate |
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35:20 | five. So that's what G protein receptor And it's activated by glued in |
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35:28 | . Now we'll talk about what it and a T. P. Is |
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35:33 | molecule but it's also a T. . Is a denizen triphosphate 80 |
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35:40 | Is also a neurotransmitter in the brain there are metabolic tropic receptors on glia |
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35:48 | are called P. Two Y one . So the metabolic tropic receptors they're |
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35:56 | linked to this G protein called G G Queer and what G. |
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36:07 | Does and astra sides is it regulates amount of calcium. It has to |
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36:17 | a certain amount of calcium and communicates calcium waves. So Glia does not |
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36:23 | with each other through action potentials, through calcium waves, sending these waves |
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36:30 | electrical gap junctions through the synopsis that electrical synopsis. They're all interconnected through |
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36:37 | electrical networks and regulating the control of specific glutamate release. So on the |
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36:46 | have a normal situation and a lot neurological disorders. And we'll be discussing |
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36:54 | in the scores a lot of times significant inflammation in the brain. In |
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37:01 | it will hear sometimes talks on Alzheimer's that says the brain on flames and |
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37:08 | talks about inflammation and one of the of inflammation is that it is in |
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37:17 | brain controlled like leo's house and it controlled this inflammatory immune response in particular |
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37:27 | controlled by micro glial cells. But the ostracized sides can play a role |
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37:36 | this process. And if there is levels of inflammation and inflammation in the |
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37:43 | can happen following a brain injury. can happen following an infection in the |
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37:49 | viral infection. Meningitis, bacterial or infection. It can be because of |
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37:59 | like I said trauma but it can potentially even a genetic or environmental causes |
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38:07 | toxicology chemicals that can cause inflammation of brain and it can lead to glia |
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38:17 | reactive and this process is called reactive sis and during the reactive reality sis |
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38:26 | is shown here on the right is in the epileptic grade. This is |
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38:33 | example where in epilepsy because of the activity in neurons you will also have |
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38:42 | aosis. And during the reactive Rios what you have is M Glue. |
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38:48 | . Five. This ion metabolic tropic receptor and it says activated microglia. |
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39:01 | micro glia are essentially over activated and are five, gets up regulated now |
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39:07 | glued innate that gets released and bind glorify on glial selves. So wait |
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39:18 | second. He first told us about . Now you're telling us about metabolic |
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39:25 | glutamate receptors. So don't confuse these with the tripartite synapse schematic. That |
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39:34 | about the cycling of glutamate. It's important glutamate in the end and how |
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39:40 | of glutamate is produced. But it is released by excitatory neurons will |
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39:47 | to Mettomo tropic receptors. Anglia. so Gloria doesn't have uh the the |
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39:57 | . Kind eight and then D. . They have metabolic tropic and glue |
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40:02 | five and in the case of reactive and inflammation you have over expression of |
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40:09 | . That means there's too much of receptor over expression a lot of times |
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40:14 | that this glia is going to start more of this protium and inserting it |
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40:22 | the number and when it does So the same glutamate levels can trigger abnormal |
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40:31 | in glutamate abnormal increases of calcium and regulation of of glutamate release from |
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40:43 | So glia control glutamate level. You to have normal function of in blue |
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40:48 | five through this G. Q. control normal levels of calcium, a |
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40:53 | cycling of glutamate. But if you regulate this is one of the mechanisms |
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40:59 | reactively aosis and you increase calcium cycling you increase the glutamate release and availability |
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41:08 | neurons. You're just perpetuating the imbalance excitation and inhibition. But now you're |
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41:14 | that imbalance through reactively aosis and through cells. So as well as reactive |
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41:26 | release TNF alpha which acts on N. F. R. One |
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41:31 | in the pathway that promotes prostaglandin. formation. Prostaglandin in turn activates a |
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41:39 | . Q couple prostituted receptor that boost astra site calcium release and thus astra |
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41:46 | glutamate release. So there's another loop and some of their nose. But |
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41:53 | are some of the cellular mechanisms by you have abnormal flux of glutamate and |
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42:01 | of glutamate exacerbating some of these disorders epilepsy but in this case from from |
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42:09 | perspective not from too much neuronal activity too little inhibition but from glutamate and |
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42:15 | from transporter but through actual intracellular cascades calcium regulation through the glue dramaturgy through |
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42:26 | glial uh cellular cascades. So it's interesting and challenges and opportunities uh major |
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42:39 | for using information. New anticonvulsants because is for epilepsy. But I think |
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42:45 | major challenges still remain for really effective that use these an M. |
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42:50 | A. And AMP kinase receptors finding of G alpha Q coupled receptors such |
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42:58 | masculine IQ. And potentially the activation America kinda receptors. So there's all |
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43:03 | of complex interactions going on in the with other chemical systems as well. |
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43:10 | so this is uh pretty pretty It's just a little bit more about |
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43:19 | physiology that we're gonna go into understanding E. P. S. |
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43:24 | S. And the conductance is. then we're gonna kind of start going |
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43:30 | the excitation and the recording of the single channel currents more of the G |
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43:38 | and then we're gonna go into inhibition to gather. So for Gaba I |
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43:45 | have a an equivalent sort of a pager. Well it's a little bit |
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43:52 | than one page. But again, we're gonna touch upon what you will |
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43:55 | responsible for the exam is pretty much for Gaba is um summarizing in the |
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44:03 | couple of paragraphs. But Gaba is major inhibitor neurotransmitter and we're going to |
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44:09 | back to this in the second or about an hour or so. So |
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44:19 | think that this diagram here just illustrates confirms what we already discussed pharmacology. |
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44:30 | have their own agonists antagonists, genetics fast early phase of E. |
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44:39 | S. P. This is really screen. I really I need to |
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44:44 | it. We'll report you screen. kinetics passports are slow selectivity selectivity for |
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44:53 | ions they conduct. So calcium always calcium sometimes throughout conductance. An |
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45:04 | D. A. Large conductance. pick a seaman's ample receptors not so |
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45:11 | , and M. D. A is blocked up with magnesium block |
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45:14 | So it's a coincidence detector. And we started discussing some of the recording |
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45:23 | . So I think because there's just a few of you in class |
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45:28 | maybe this could be a good stopping on uh odometer GIC physiology. Because |
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45:36 | we go and into more glue dermatologic recording methods. We will talk about |
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45:46 | cellular versus wholesale recording methods and some the experimental techniques that we use in |
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45:54 | lab. And then as far as will probably spend uh maybe 45 minutes |
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46:03 | so to an hour in Gaba. we'll continue, we'll call it uh |
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46:10 | in eight Uh dermatologic three and then go into urgent. Okay so this |
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46:18 | conclude today's |
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