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00:02 | So this is lecture 13 of neuroscience I'm on Uhh video points. I'm |
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00:08 | you that all of your materials have there. I think that now you |
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00:13 | see that there is a display of on most of the lectures so you |
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00:17 | scroll through the slides and literally within to 10 minutes to remind yourself all |
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00:23 | the material that you studied the lecture or a week before you can review |
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00:28 | two lectures for example. So we in great detail the common ergic signaling |
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00:34 | Colin ergic system and you will be for all of the enzymes involved in |
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00:40 | , degradation and all of the details we discussed, including Alzheimer's medications that |
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00:46 | statistical in history's inhibitors and such. so we talked about distinguishing the neuro |
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00:56 | junction from the central nervous synapses. we said that neuro muscular junction have |
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01:03 | very powerful inflate potential and the single will release enough neurotransmitter will generate strong |
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01:10 | of the post synaptic response in the muscle cell for it to produce an |
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01:14 | potential and contract the muscle fiber. in the central nervous system we have |
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01:21 | small E. P. S. . S excited her personality potentials very |
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01:26 | I PS PS. And they sort cancel each other out. And so |
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01:30 | have to have a significant enough excitatory significant enough number of excitatory synapses to |
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01:38 | activated in order to evoke person optically response involves synaptic response. And we |
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01:48 | about I wanna tropic versus Meadowbrook tropic . Last lecture we looked at the |
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01:56 | arctic neuro pharmacology, distinguishing nicotine IQ mask your enic acetylcholine receptors. And |
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02:04 | at the neuro muscular junction you will have nicotine acetylcholine receptors and only and |
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02:09 | to have a positive response. Deep in the muscle. And as we |
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02:14 | masculinity receptors can actually cause a different effect at the level of the |
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02:20 | So if the acetylcholine binding to nicotine receptor will cause deep polarization binding of |
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02:29 | cyclical into masculinity, G protein coupled will cause a hyper polarization because through |
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02:36 | jew protein complex it will open the channel so which one will win. |
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02:42 | don't know. But temporarily nicotine acetylcholine will win the polarizing missile and then |
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02:49 | some delay because of the metal bar signaling. Some tens of milliseconds |
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02:55 | You will engage another metaphor tropic potassium channel opening and hyper polarization instead |
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03:02 | deep polarization. So we also talked cata cola means uh and mono means |
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03:10 | general. We talked about serotonin and talked about their breakdown so subtle Colin |
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03:18 | broken down in the synaptic cleft by asteroids. Mono means okay the other |
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03:25 | cola means in serotonin actually re uptake back into the present at the cleft |
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03:32 | then they're neutralized by oxidation with Amine oxides which hangs around the |
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03:39 | the membranes of the mitochondria mitochondria are prevalent in these pre synaptic terminals. |
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03:46 | need a lot of mitochondria to generate and a tPS needed in order to |
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03:51 | and prime the vesicles at the pre active zones. And this is the |
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03:56 | function is that the mitochondrial membranes will laden with this enzyme that will be |
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04:05 | cata cola means and rendering them basically them down further than it takes time |
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04:14 | re synthesize them and then upload them . So we know that this is |
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04:22 | different from the seed alkaline, although in the way of the neural transmission |
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04:29 | reloading of the of the bicycles and . The neuro peptides are different because |
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04:34 | in secretary Granules as we discussed So we discussed serotonin and we discussed |
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04:46 | pharmaceutical preparations and drugs and illicit drugs would target some of these transporters for |
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04:53 | cola means signaling or serotonin signaling. talked about in the cannabinoids talked about |
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05:01 | ways of studying neurotransmitters and neurotransmitter You can study different components using |
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05:11 | immune, artistic chemistry, radioactively labeled sensitive hybridization. Your transmitter mimicry with |
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05:19 | electrode dialysis or neurotransmitter mimicry with UNQ of the neurotransmitters of interest using laser |
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05:30 | . It's very fast speeds with very spatial resolution. So all of these |
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05:35 | may show up asking you some questions the quiz or on the exam. |
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05:41 | talked about synaptic integration and how does soma here integrates the information that comes |
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05:49 | and we talked about the spatial summation will immediately cause a very large response |
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05:57 | optically and we talked about the temporal which will cause a much larger response |
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06:03 | not as large as a spatial but that post synaptic response due to |
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06:09 | temporal summation will be prolonged, still any further inputs that would be excited |
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06:16 | into the cell. Or dipaula rising the cell, still having a positive |
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06:21 | facilitate ori effect on those talked about length constant which is essentially the distance |
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06:28 | the peak current injection here and as measuring the speed current injection right here |
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06:34 | the site of the injection, You 100% maximum current. And how what |
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06:40 | , How far can this current travel dendrites And Soma is because they are |
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06:45 | myelin ated. There's no regeneration. will be certain current loss over distance |
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06:54 | if the current is small it is the distal distal dendrite, that current |
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07:00 | travel and by the time it reaches will be negligible and size, that |
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07:05 | polarization or even hyper polarization. So distance At which discouraged from the maximum |
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07:14 | goes down to its 37% value. distance is referred to as the length |
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07:20 | lambda. And the long length constance promote the flow of that current over |
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07:27 | distances and short length constance would result that current in that curve being steeper |
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07:34 | that current dying down over a shorter . We also talked about inhibition and |
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07:46 | inhibition and in general the principle that and inhibition and excited or an inhibitory |
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07:53 | will be competing for the attention of cell that is integrating the signal and |
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07:58 | post synaptic cell and that if you strong inhibitory inputs that are close to |
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08:04 | selma and remember the selma is where information is integrated. It's an integrative |
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08:10 | of the neuron and the axon initial is where the action potential is |
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08:16 | So if you have strong inhibition close the selma, to these regions, |
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08:21 | inhibition will negate the deep polarization or excitation that might be generated more |
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08:29 | One of the ways that does it does it through what we call |
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08:33 | shunting inhibition. Then we moved on reviewed again all of the neurotransmitter systems |
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08:40 | we were talking about. And I that we talked about metabolic tropic signaling |
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08:47 | we talked about metabolic tropic acetylcholine receptor in this case. And this is |
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08:54 | example of how metabolic tropic acetylcholine receptor will cause the opening of the potassium |
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09:04 | and the potassium channel opens. You , there's a lot of potassium inside |
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09:07 | cell that positive ion positive charge will the cell and the cell will be |
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09:13 | polarized. So this is the physiological and the molecular mechanism behind the medical |
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09:23 | signaling glutamate and gaba the major excitatory inhibitory neurotransmitters and glutamate, as we |
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09:32 | as a part of this tripartite synapse that astra sides real cells control the |
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09:42 | and cycling of glutamate and can affect activity between the tunes are connected |
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09:49 | So we looked at an example where am the tropic. Acetylcholine is de |
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09:56 | , minimal tropic is hyper polarizing. different mechanisms and they can be co |
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10:01 | and co expressed on the same cells the same nearby patches of the |
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10:07 | You can also have competition amongst the tropic signaling receptors. And such competition |
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10:14 | described in the case of norepinephrine, beta norepinephrine receptor having Gs stimulatory G |
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10:22 | and promoting the production of cycling campion kindness. They pushing to produce more |
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10:30 | on the opposite side here binding off to alpha two receptor with pulled the |
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10:37 | away from producing more of the cyclic and more of the protein kindness. |
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10:44 | recall that kindness is famous for elit they contribute this P. 04 |
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10:49 | They donated two receptor proteins and quite these P. 04 groups make these |
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10:58 | and channels more active and phosphate aces phosphor aly the uh the pac man |
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11:05 | chews up the P. 04 group for late and quite often defense correlation |
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11:11 | lead to reduction and function along that protein or that pathway. So inside |
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11:17 | cells you have these layers and levels kindnesses and prospectuses signaling with certain spatial |
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11:27 | of course dependent on the location of G proteins and their complexes. So |
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11:35 | will ask you questions on the exam on potentially quiz on some of these |
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11:41 | nuclei in the brain stem. So that norepinephrine was produced by local |
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11:48 | The blue nucleus, interestingly enough when cells are exposed and norepinephrine cells are |
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11:56 | to oxygen to actually turn blue so does appear bluish under a microscope. |
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12:03 | serial lius. These are the these are the only soulless in the |
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12:10 | cns that will produce norepinephrine and then axles from these selma's, what we |
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12:19 | are very diffused and they're often called sprinkler systems of the cortex because they |
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12:28 | diffuse lee project those axons and diffused Sprinkle neurons and circuits in the cortex |
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12:36 | norepinephrine. If you're talking about serotonin will come from the raft nuclei. |
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12:43 | will get sprinkled and so we are to get to the specificity of this |
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12:49 | of course the specificity and the specificity the response depends on what these post |
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12:54 | neurons that are being sprinkled or open and express. Do they express beta |
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13:01 | by beta stimulatory or alpha two Different subtypes will express different subtypes of |
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13:08 | medical tropic receptors. Also different levels these medical tropic or anna tropic |
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13:14 | So recall that I want to stay for a second if you were for |
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13:29 | to take local Sibelius out there would be in northern africa synthesized anywhere else |
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13:37 | the brain. So this is how confined Now if you were to take |
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13:42 | chunk of cortex out there would still gaba and glutamate synthesized everywhere else where |
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13:51 | didn't remove that jump, you So so this is this is really |
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13:55 | difference in what I said is if think about excitation, let's say it's |
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14:02 | . Inhibition is black, then the systems and these neurotransmitters, acetylcholine mono |
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14:08 | other things. They add all of color or grayscale if you may to |
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14:13 | black and white and make the whole in the brain more interesting. The |
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14:19 | by which neurons learn can change with neuro modular torrey substances and they can |
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14:25 | the balance of excitation and inhibition in brain. And if you have the |
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14:30 | imbalance along serotonin ergic pathways. Ah you're looking at the neuropsychiatric disorders, |
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14:40 | disorders, anxiety disorders, this is disorders that would be associated with those |
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14:47 | and those camera films. If you're at loss of acetylcholine neurons and Colin |
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14:52 | central tone and aging population, you're at a concern of Alzheimer's disease. |
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15:03 | you look at Parkinson's motor neurological disorders have motor dysfunction component. Ah There |
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15:13 | be dopamine dysfunctions. You know, disorders like schizophrenia also has a dopamine |
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15:20 | and one of the dominating hypothesis of is imbalance of dopamine receptors you want |
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15:27 | D to the ratio of those and cannabinoids are different because they're not packaged |
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15:34 | vesicles and what happens is that they produced on demand, their lipid soluble |
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15:41 | signal retrograde lee. That means they from post synaptic side into the pre |
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15:46 | terminals and through the G protein coupled at the pre synaptic terminals that are |
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15:52 | with the CBD cannabinoid receptors one and control the release of glutamate and gaba |
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15:59 | the pre synaptic terminals. So you when we can have notes, balanced |
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16:03 | levels of the excitation and inhibition whenever levels increase and there's too much there's |
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16:10 | much stress, there's too much of for example, too much glutamate can |
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16:16 | to what is called glutamate. Excitatory . Too much glutamate will mean too |
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16:21 | calcium prison optically. That means a of action potentials. A lot of |
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16:27 | prison optically. A lot of glutamate . That means a lot of calcium |
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16:31 | optically and glutamate excited toxicity. Too excitation can lead to toxicity. Too |
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16:38 | excitation can lead to too much calcium . If it's unregulated inside the |
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16:44 | most of the calcium in the cytoplasm not floating around freely gets bound up |
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16:49 | all of these calcium calculators and calcium proteins. But you have too much |
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16:54 | that calcium go up. It also be toxic but also can upset the |
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17:00 | of these intracellular molecular signaling cascades and promote calcium induced calcium release from the |
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17:07 | and turn on this vicious cycle. having molecules like cannabinoid receptors having other |
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17:14 | pre synaptic li like a dentist in having pre synaptic aly gaba B receptor |
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17:20 | you'll see later today helps regulate the synaptic neurotransmitter release. But in particular |
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17:26 | the cannabinoids, the gasses and now C. O. They will function |
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17:30 | this retrograde fashion and control activity on pre synaptic side despite their production on |
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17:36 | pasta topics side a lot of times can view this as a negative feedback |
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17:41 | . So negative feedback like an air . Right? So too much |
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17:46 | You turn down the heat you turn in the sea and this is the |
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17:53 | important function of the other cannabinoids in brain. Mm hmm. So we |
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18:05 | here. Okay do we discuss things cannabinoids? Deep polarization induced suppression of |
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18:13 | for control of gaba release. Deep induced suppression of excitation for control of |
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18:20 | release. We also saw that the excitatory neurotransmitter glutamate is one enzymatic reaction |
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18:29 | . Deeper box elation by the atomic , deeper box list removal of this |
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18:34 | group here into the major inhibitory neurotransmitter . You'll also learn today that when |
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18:42 | first studied glycerine in the spinal we said that listen is the major |
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18:48 | neurotransmitter in the spinal cord. It's by the inhibitory into neurons in the |
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18:55 | cord. But today you will learn glycerine is also involved and excited to |
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19:03 | signaling in the C. N. . In the in the high order |
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19:10 | all of the inhibitory into neurons and and the Hippocampus. This varieties of |
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19:19 | that we were looking at 21 different of inhibitory neurons. They will all |
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19:25 | for God what time of casa speaker ? They'll all be still containing different |
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19:34 | cellular markers. They'll still have their anatomy, their dialects and actual |
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19:40 | All the good things that you learn they will all be released in Gaba |
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19:46 | they might still be co expressing some the peptides. So they will be |
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19:51 | Gaba and some of the statin for so they can co express and co |
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19:58 | these. Remember there's differences when you the neuropathy ties in the whole bio |
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20:04 | trafficking and release of them that is from the secular mechanisms. Glutamate gets |
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20:14 | into neurons and so this Gabby get so they have transporters into neurons and |
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20:21 | they have transporters into vesicles. When think about interesting therapeutic strategies, these |
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20:26 | very difficult therapeutic strategies. But can affect the loading properties after the secular |
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20:35 | transporter? I'm not saying there's an to it. I don't even know |
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20:41 | there is a drug there but so we've learned that we control most of |
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20:45 | things that the synaptic cleft by degrading chemicals in the synaptic cleft war by |
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20:51 | re uptake of these chemicals prison optical more difficult by chemical neurological treatment strategies |
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21:01 | concern While let's just affect let's say transporters can we do that instead of |
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21:10 | we actually block something out? So , remember when you think about the |
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21:16 | systems it's a system from pre synaptic loading release post synaptic effect degradation of |
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21:25 | synaptic cleft and recycling and so a of the a lot of these parts |
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21:32 | be employed for therapeutic strategies and drug . So let's talk about we don't |
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21:40 | Nero pharmacology. These are three iron tropic glutamate receptor channels the major ones |
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21:50 | the C. N. S. Tampa and MGmt Nate glutamate is an |
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21:55 | to all of them. Glutamate is endogenous agonists that we produce to all |
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22:01 | them. And then you have chemical that will distinguish them Bubble Banter Apple |
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22:09 | in MD 80 and MDA. Kinda kinda interceptors they will also have their |
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22:15 | distinct antagonists as well. So what the pharmacology and how is this |
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22:23 | P. S. P. So when there is glutamate release and |
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22:29 | here are these little green molecules when gets released from the pre synaptic terminal |
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22:38 | will bind to both Tampa and an . D. A receptor is by |
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22:42 | way ample and Canaanite are quite often together because of their similarities and their |
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22:48 | and uh and responses and an D. A. Is there's a |
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22:55 | a bit of an oddball so the receptors are shown here in blue and |
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23:01 | receptors are shown in pink and these molecules are glycemic molecules. So when |
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23:11 | goods released and glue mate will bind both happen, NMDA receptors, Albert |
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23:22 | will actually open immediately and they will conducting sodium inside causing the initial deep |
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23:31 | of this excitatory post synaptic potential. looking on the post synaptic cell. |
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23:36 | post synaptic responds. How does The PSP comes about? What |
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23:42 | This is a collective change in the and potential E. P. |
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23:46 | B. This is Andy PSP excited passing up with potential. We now |
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23:55 | that there is a number of glutamate . So what we know is this |
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24:03 | phase of E. B. Be is generated by AMFA receptors and |
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24:12 | late phase the E. P. . B. It's generated by an |
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24:18 | . D. A receptors. So M. P. S. |
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24:22 | Is a composite response of deep polarization re polarization through both Tampa and an |
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24:33 | . B. A type channels. difference is the following. While glutamate |
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24:39 | to ampara reception, it will immediately the upper channel cause the influx of |
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24:45 | causing the initial depressurization and I'm the receptor it's not going to open immediately |
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24:53 | N. M. D. A has a magnesium block. In fact |
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25:00 | has both magnesium and zinc blocks. there's two cat ions. Mg two |
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25:11 | Magnesium two plus that is blocking the one that is blocking this poor after |
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25:19 | receptor channel and the only way that channel can open is if you remove |
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25:27 | magnesium from from this channel and in to remove the magnesium the membrane potential |
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25:36 | to de polarize. So what happens when glutamate initially binds the ample |
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25:44 | it d polarizes the numbering potential that for the magnesium to be removed from |
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25:51 | NMDA receptor. Then an M. . A receptor opens. And as |
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25:56 | can see an M. D. receptor will be conducting sodium inside also |
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26:02 | de polarizing the self but also most calcium. It's very important source of |
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26:10 | of calcium through NMDA receptors important for cascades, important for learning important for |
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26:17 | plasticity that we've discussed from the beginning of course the re polarization through both |
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26:24 | channels will happen when potassium subsequently too polarization. The potassium will now leave |
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26:31 | cells re polarizing um to this initial in potential before the BsB. So |
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26:39 | membrane potential of minus 65. An . D. A receptor has magnesium |
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26:45 | And only if you d polarize these to -40 -35 -30. That's when |
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26:53 | NMDA receptors will open. Two. there are distinct differences. This does |
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27:03 | make an M. D. A um edible tropic receptor. They're all |
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27:07 | tropic receptors. This is an example on the right of metabolic tropic glutamate |
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27:14 | which is linked to g protein complex signals through a molecule called phosphor |
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27:20 | A sea of PLC. So an . D. A receptor is a |
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27:26 | its eye on a tropic. This quite often missed by students. They |
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27:31 | that because ample opens immediately it's on tropic and because an M. |
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27:35 | A. Has a magnesium block it's of a tropic. It's not metabolic |
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27:40 | is only if it's linked to jupiter complex. These receptors are channels Tampa |
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27:48 | India receptors are channels G protein complex are not channel. So binding of |
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27:55 | and metabolic tropic glutamate receptor will not the channel in the middle of the |
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28:02 | receptor because there is no channel it just activating downstream cascades through the jew |
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28:08 | complex. So now you have non . M. D. A. |
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28:12 | is an MBA. And kind And have certain differences between 20 PICO Seamus |
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28:18 | that? We talked about conductance is and we talked about relevant scales of |
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28:24 | is So this is how much a ample channel will conduct. About 20 |
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28:29 | emails of current An M. A receptor on the other hand will |
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28:34 | 50 PICO cements. So who has conductors who can put in more positive |
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28:41 | as an M. D. A . But you have to wake it |
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28:44 | you have to de polarize the cell remove the magnesium block. They have |
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28:49 | own antagonists or specific blockers. And it receptors are blocked by a substance |
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28:56 | C. N. Q. And an M. D. A |
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28:59 | is blocked by a substance called a . So this is important. We're |
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29:06 | learning agonists. Remember for nicotine nick nicotine, Azizi mascara nick, there's |
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29:14 | mask urine for civil Colin receptors. the antagonists, nicotine IQ is |
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29:23 | masculinity is atropine, we use all questions. These are agonists again. |
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29:31 | is easy and it is an An M. D. A. |
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29:34 | an M. D. A. an agonist kindness, kindness is an |
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29:37 | . Glutamate is an agonist for all of them. It's natural endogenous substance |
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29:42 | bind them differently and then they have own antagonists. So mostly will be |
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29:48 | for knowing this an M. A receptor antagonist because it shows up |
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29:51 | a very important graph that we're about discuss. NMDA receptor is dubbed as |
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29:57 | coincidence detector because it coincidentally has to the release of the pre synaptic neurotransmitter |
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30:06 | binding of that neurotransmitter glutamate to the of the truck and post synaptic deep |
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30:11 | which gets generated through ample receptors. it only gets engaged if there is |
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30:18 | of the post synaptic deep polarization. it's coincidentally detecting pre synaptic activity. |
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30:24 | and post synaptic activity deep polarization only it engages. That's very important in |
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30:31 | feature coincidence detection feature an influx of through an MD. A receptors very |
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30:39 | for plasticity for strengthening the synapses for the synapses more efficacious stronger and learning |
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30:50 | the brain. Now an M. . A receptor because it takes time |
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30:57 | it to open up is responsible for late portion of the E. |
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31:03 | S. P. And Apple receptor responsible for the early portion of the |
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31:09 | being most of the AMP A non receptor sample key Nate will allow for |
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31:17 | of sodium and the flux of potash . But all in MD A receptors |
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31:24 | allow for influx of calcium. So some complicated receptors but all in NBA |
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31:33 | they pump calcium in this is where comes into play. Glycerine is a |
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31:42 | factor that the NMDA receptors. That that glutamate when it binds to the |
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31:50 | receptor. If glycerine is there is co factor it makes sure that this |
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31:55 | of glutamate, NMDA is really good strong and in the absence of glycerine |
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32:00 | a co factor this is in the not in the spinal cord. The |
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32:05 | of glutamate is not as efficacious. N. M. D. A |
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32:10 | . And so like I seen in inhibit their into neurons and the spinal |
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32:16 | is inhibit their neurotransmitter. But when binds to NMDA receptors in the CNS |
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32:22 | a co factor. Okay this is binding sign for magnesium There's also you |
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32:30 | see there's a binding side for zinc titanium zinc two plus. And these |
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32:37 | receptors will have many different binding It's a site for therapeutic targets for |
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32:46 | drugs. It is also can be by illicit drugs and and then the |
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32:55 | receptor one it is over activated by like PCP crystal methane and such can |
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33:06 | not only hallucinations but can induce acute that can become chronic schizophrenia from just |
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33:14 | few or even a single dose of of these very potent drugs. So |
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33:21 | all about the dynamic range of the . This is a great dynamic range |
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33:27 | the system to learn activated with endogenous , maybe some pharmaceuticals to to repair |
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33:34 | system. But if you pull that too far out of its dynamic range |
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33:41 | can happen with illicit drugs that have stronger binding properties to these receptors. |
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33:48 | happens to that rubber band it snaps it's no more so in all of |
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33:55 | systems it's like that serotonin has its dynamic range of functions and the phenomenons |
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34:02 | their own dynamic range of functions. of them have a better set boundaries |
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34:07 | this dynamic range so it doesn't let that string to be pulled too far |
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34:13 | string or rubber others are more susceptible other systems. Chemical systems and receptors |
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34:21 | more susceptible to to pulling and it on the substances of buying to |
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34:27 | Okay and uh MK 21 that I here is an interesting antagonist so some |
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34:35 | will buy into an M. A receptor no matter what whether it's |
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34:38 | or closed MK 80. 1 Is antagonist that will bind to only open |
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34:44 | MD 80 or so. So again what's the difference between closed and um |
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34:53 | interceptor and open an M. A receptor? The confirmation will change |
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34:58 | something that opened up in this protein channel. Maybe there is an opening |
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35:06 | that can receive another molecule and the change another molecule can have access now |
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35:11 | buy into sequence of amino acids from protein. Okay so now we come |
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35:17 | to this concept of voltage clamp. that we can control the voltage, |
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35:23 | can clamp the voltage. And if record and MDA receptor currents and these |
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35:29 | deflections downward deflections and upward deflections is opening And current flux is through NMDA |
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35:37 | and its physiological magnesium concentrations extra cellular you have about $1.2 million dollar |
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35:45 | And at these physiological magnesium concentrations you see at minus 60. There's barely |
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35:51 | opening, there's barely any flux. of these deflections that represent flux through |
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35:57 | M. D. A channel and . D. A channel currents. |
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36:00 | you de polarize the cell to -30 can see that there is a lot |
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36:05 | of an NMDA receptor and it's starting open fairly well. The reversal potential |
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36:11 | equilibrium potential in this case the reversal for an M. D. A |
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36:17 | is zero million volts. Remember what potential is. This is our ivy |
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36:28 | Ivy, this is -60 plus Yeah this is minus one. Yeah |
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36:39 | know out there plus one another up and so This is the reversal is |
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36:50 | mila vaults. Remember we looked at potassium curve I. V. |
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36:57 | this is potassium I. V. . It reverses about -80 million volts |
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37:04 | . Mm hmm. So now you no current flux at zero motive. |
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37:09 | when you de polarize and lock that potential to positive 30 you see a |
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37:14 | more of the flux, positive Very very robust flux. In fact |
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37:20 | seems that an M. D. receptor just by looking at these traces |
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37:25 | recordings prefers to conduct in that opposite in the upward direction. Remember we |
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37:33 | that not all of these I. curves are linear. A lot of |
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37:39 | are rectifying or they have different shapes multiple kind of a bumps if you |
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37:49 | when they're active and when they enacted this on the right there's a physiological |
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37:55 | in which you remove magnesium zero magnesium the system. Now what does that |
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38:01 | ? That means that there's nothing blocking receptor. If there's nothing blocking NMDA |
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38:07 | and you release glutamate boom at minus you see a very strong response and |
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38:14 | 30. You see still a strong then at zero you see nothing that's |
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38:19 | the current reverses for an M. receptor and then again you see strong |
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38:24 | D polarized holding membrane potentials. This proves that magnesium block is holding an |
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38:32 | . D. A receptor. So you remove magnesium NMDA receptor can be |
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38:37 | at hyper polarized potentials. This kind a Condition, physiological condition of zero |
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38:47 | will evoke seizures and epilepsy. So you don't have proper levels of magnesium |
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38:54 | proper blockade of an M. A receptor channel and glutamate is |
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38:58 | an M. D. A receptor on check. It will cause way |
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39:02 | much deep polarization that can cause abnormal neuronal networks, abnormal signaling and evoke |
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39:13 | electrical activity. We call seizures or seizures and neuronal circuits. This is |
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39:19 | Model zero Magnesium as an experimental model generating seizure like activity in vitro and |
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39:28 | viva as well. So it's all the balance of that system. You |
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39:34 | that magnesium in there, wow. . And now we're going to talk |
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39:41 | the ivy plots for Ampara Skynet and receptors. So in this case, |
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39:50 | we're doing is we're using voltage we're going from minus 80 minus 42 |
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39:56 | 20 million volts and we're stopping every or so million volts along the scale |
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40:03 | and we are measuring the early So this artifact here is glutamate release |
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40:09 | stimulation of glutamate. And we're gonna this line here some five milliseconds later |
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40:17 | the glutamate release. And this is be our line that measures the peak |
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40:22 | and the early component of the P. S. P. And |
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40:26 | we're gonna draw a second line The second dash line, let's say |
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40:31 | 10 milliseconds later. And that line going to measure the current fluctuations that |
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40:38 | some 20 milliseconds after the glutamate So this way we can monitor the |
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40:45 | component measure the early component and the components. We're using a voltage clamp |
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40:52 | equals Ir we're clamping the voltage therefore measuring the current. This is the |
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40:58 | fluxus, this is an inward current at -80 you can see that this |
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41:03 | current is very sharp with a very recovery. So at -80 if you |
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41:10 | the early component here you have a deflection. Early component -40. Still |
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41:17 | plus 20 is still there. And is the linear line here that represents |
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41:23 | Tampa I. V. Curve. of these triangles here represents the |
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41:30 | Curve for ample receptors. So ample channels and this early component for which |
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41:38 | is responsible is the linear component of . P. S. P. |
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41:44 | it has linear I. D. with a reversal potential at zero military |
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41:52 | aren't you? Glad you learn things I. D. Plots. Now |
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41:55 | will say. Okay that's really interesting when we studied the reversal for potassium |
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42:01 | was acqua Librium potential for potassium It's zero. No evolves for ampara |
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42:08 | . What ions this amp a receptor , it conducts sodium M. And |
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42:15 | out. So now this reversal potential the receptor channels reflects multiple ionic species |
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42:25 | sodium and potassium. And in fact seeing that zero Mela vaults. Remember |
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42:31 | sodium equilibrium potential is positive 55 And potassium equilibrium potential is negative 80. |
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42:39 | actually it's biased toward sodium. The His bias towards sodium because it allows |
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42:45 | sodium to flux in through it has stronger conductive power through sodium, so |
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42:51 | speak. And then when we measure late component at -80 -100 -80. |
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42:59 | are the closed circles here, we're seeing much current. But then when |
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43:04 | de polarize the cell to -55 -15 year. We are seeing now this |
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43:14 | component here. We're seeing this late component and that's an MD. A |
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43:21 | and you can see that NMDA currents disclosed circles are nonlinear. They're reversed |
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43:28 | million balls and they are rectifying in outward direction. Remember the currents at |
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43:34 | negative our inward currents of the positive ampere values are outward currents by |
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43:43 | And the last part of this curve what happens if we apply a |
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43:49 | A PV is N. M. . A receptor antagonists. Remember we |
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43:54 | that there's agonists and antagonists, A is an M. D. A |
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43:58 | antagonist. When we apply a this blue line under the curve is |
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44:06 | . So instead of having this top here. Okay, the late current |
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44:11 | now block the late current and if block the late current with a |
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44:17 | V. You can now see if affected the early components. So the |
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44:21 | or the open triangles is the early . You see that A peavey doesn't |
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44:26 | the early component at all. But a PV blocks the late component and |
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44:32 | are the open circles and so now have essentially zero this line down to |
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44:38 | zero current value. Of course there some residual uh deep realizations and cars |
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44:45 | this is the open circles and instead this nice closed circle shape and |
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44:49 | D. A. Car you know it and you have zero current. |
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44:54 | now this is another demonstration how you use a voltage clamp. Remember how |
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45:01 | Narahashi had the tetrodotoxin and he needed use the voltage plan to isolate sodium |
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45:07 | potassium currents while the Hodgkin and Huxley sodium and potassium current during action |
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45:14 | And then Toshio Narahashi had the toxin had to isolate the sodium current and |
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45:19 | it to definitively showed that it just the sodium current, not the potassium |
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45:24 | . So this is a similar type experiment but now it's within the context |
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45:29 | the I. D. Plots and potentials for these receptor channels that conduct |
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45:34 | potassium and in the case of an . D. A receptor sodium potassium |
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45:38 | calcium understood. Okay so again an . D. A receptor is responsible |
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45:45 | the late current. A PV will that late current. It will not |
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45:49 | the early component at all. And component is the linear component Tampa and |
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45:56 | late component is an M. A. It's a nonlinear component and |
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45:59 | nonlinear because it has a magnesium blockade that magnesium is blocking keeping the current |
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46:06 | zero until the membrane potential D polarizes minus 50 or so. And that |
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46:12 | is now kicked out of an D. A. Receptor. So |
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46:17 | talk about calcium permeability and amping In fact this is very interesting lesson |
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46:25 | you have this very complex sequence of structure which is ample receptor channel and |
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46:34 | M. One M. Two, three and M. Four uh |
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46:40 | And in unedited version if there is . Or glutamate, ample receptors can |
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46:47 | permeable to calcium. But if you this really very long sequence complex sequence |
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46:54 | this one spotted em to replace With our which is argentine, you |
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47:01 | the flux of calcium throughout for So certain ample receptors will not allow |
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47:07 | flux of calcium and certain ample receptors will allow the calcium influx if there |
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47:15 | if they're unedited so to speak. this is an experiment this is glutamate |
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47:20 | . You're measuring glutamate to applying glutamate . This is sodium current and you |
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47:27 | see very strong sodium current following glutamate hmm And this is calcium current through |
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47:34 | M. D. A receptor. you're using voltage clamp don't worry about |
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47:38 | holding potentials. But you know how isolate sodium current, you know how |
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47:42 | isolate castle current and you see both you're using this Q version of ample |
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47:51 | but if you have the r version version of apple receptor, your black |
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47:57 | , you still can see very nice current but now there is no calcium |
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48:02 | through that channel. So this just you how you can take one Chair |
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48:07 | of the building and determine whether that is going to be permissible to calcium |
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48:13 | not major, major not just ion also secondary messenger inside the south on |
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48:23 | ginny. In early development there is an NMDA receptors in the synopsis. |
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48:29 | there are a lot of times referred silence in absence because you need to |
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48:34 | stimulate them very very strongly and activate channels. There's no amperage suffers to |
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48:40 | polarize so they're silent until ample receptors inserted and early during the development a |
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48:48 | of synapses will have an M. . A receptor without anti receptions and |
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48:52 | the composition of those NMDA receptors. have these subunits called an R. |
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48:57 | A and R. To be there be shifting during the development. This |
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49:01 | what's referred to as a not a of receptor ontology nears functional ontology any |
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49:08 | location and activity dependence, ample receptor past and these these receptor subunits their |
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49:18 | changes as a function of the development then as a function of the |
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49:22 | You will have a lot of ample that are located extra cellular early and |
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49:26 | ample receptors may be imported into the sides. Extra synaptic aly I mean |
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49:33 | extra cellular early and they will be into the synopsis. So amber receptors |
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49:38 | move really fast. L. P. Stands for long term plasticity |
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49:43 | long term potentially ation or strengthening of synopsis and influx of calcium and coincident |
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49:50 | by an M. D. A are very very important concept for |
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49:56 | Recall that these are ion a tropic receptors, metabolic tropic glutamate receptor signaling |
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50:02 | this pathway through P. I. . Two that is a membrane bound |
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50:07 | can activate this jew podium complex that now through possible. I pay see |
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50:13 | this molecule into I. P. which is a non hospital triphosphate |
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50:19 | P. Three combined to the eight . P. Three receptors that are |
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50:26 | channels on the smooth ectoplasmic particularly and further intercepted the calcium leads. Okay |
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50:34 | I. P. Three and binding can generate intracellular calcium three. And |
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50:38 | calcium stores the second component of that . A. G. Which is |
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50:43 | absolute glycerol will remain membrane bound and activate another molecule protein kinase C. |
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50:52 | um you have divergence of the pathway the membrane one element going into cellular |
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50:59 | one element remaining membrane bound and uh can activate core module and kindnesses and |
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51:09 | the kindnesses post for a little phosphate defrost correlates. So you will be |
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51:15 | these molecules through the measurable tropic signaling . But this is a pretty common |
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51:21 | tropic ultimate receptor activation. Mhm. Gaba a gobble. When Gaba binds |
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51:31 | Gaba channel, what happens is there a flux of chloride. So when |
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51:37 | binds a chloride channel, Gaba a iron a tropic receptor channel, it |
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51:42 | cause the influx of chloride. You have Gaba be measurable tropic Gaba receptor |
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51:51 | and that can regulate potassium channels and channels. It can open potassium channel |
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51:58 | it can close calcium channels through this and complex. So you have Gaba |
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52:06 | psychotropic Gaba b metabolic tropic receptor, A. As I am a tropic |
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52:12 | and flux in the fluoride will inhibit cell activity will hyper polarize, the |
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52:17 | activity will make it more negative. is the binding of Gaba and this |
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52:23 | a receptor is also target too many different substances, pharmaceutical substances and also |
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52:33 | margarita. At the happy hour ethanol bind to Gaba A receptors. So |
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52:42 | first drink causes a little bit of as well as the person down The |
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52:49 | 1, maybe also. And then there is too much activation of ethanol |
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52:55 | inhibition it goes through disinhibition process and the time you're having a third or |
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53:01 | drink, your climbing up and dancing the table all the division was |
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53:07 | So the cycles and the and the effect of alcohol in the brain and |
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53:13 | it changes goes through different stages. this is the receptor that will be |
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53:18 | as the gaba A receptor. Uh benzodiazepines, you will be hearing rap |
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53:25 | . Benzos got some benzos so that are benzodiazepines. So those are pharmaceutical |
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53:33 | and of course you know sometimes they their way in the streets ah the |
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53:40 | because they kind of a slowdown in in the brain inhibit activity in the |
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53:47 | . But benzodiazepines are also very potent medications that are used to boost inhibition |
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53:56 | are very common and still perhaps one the most effective drugs at stopping epileptic |
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54:04 | . Benzodiazepines are very commonly used. when you hear the hip hop songs |
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54:11 | about something else using it for something . Barbiturates um neural steroids also have |
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54:21 | sites to gather receptor Gaba A receptor this case Gaba B. When Gaba |
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54:31 | stood and opens the potassium channel and causes hyper polarization. So if you |
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54:38 | chloride channel you cause hyper polarization and G protein complex if you open potassium |
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54:44 | potassium positive islands, leaving well also hyper polarization. So this is sort |
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54:51 | a before I get to that I look at this traces here where you |
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54:57 | typically you stimulate and you will see excitatory response E PSP. This very |
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55:03 | excitatory response. This is actually from recordings when I was a graduate |
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55:09 | So I would see this very strong . P. S. B. |
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55:13 | it was very sharp and it was by Gaba A. And Gaba |
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55:18 | Because it's conducting chloride. It's trying drive the number in potential too equilibrium |
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55:24 | for chloride. And then Gaba Is hyper polarizing the member and further |
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55:32 | opens the potassium channel and tries to the number of potential. So the |
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55:41 | inhibition is Gaba A. And the inhibition is Gaba B. Gaba B |
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55:46 | be even further hyper polarized. So this case I wanna tropic Gaba and |
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55:52 | tropic are causing the same physiological Fanatical. There's various combinations of these |
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55:59 | that we talked about and what I is actually I would like to probably |
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56:05 | is the last slide and very brief about g protein coupled receptors. I |
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56:13 | leave it actually to the next I'm not going to rush through this |
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56:17 | I would highly recommend that you look this diagram, you won't have to |
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56:22 | it. But it's really really explains lot of things that we talked |
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56:26 | It looks at the glue dramaturgical excitatory . It looks at the Gaba ergic |
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56:32 | synopsis. It has these things that already know post synaptic densities Gabba. |
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56:39 | be potassium channel calcium channel N. . D. A receptor. And |
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56:43 | when we come back next week on we'll put all that we've learned about |
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56:49 | excitatory glutamate ergic signaling inhibitor dramaturgical signaling this diagram. So you understand the |
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56:57 | at the level of these communicating excited inhibitor synopsis. Quickly review the jew |
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57:04 | coupled complex S Types of the receptors you have and then we will move |
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57:11 | c. n. s. so expect. Maybe we'll spend another 15 |
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57:15 | 20 minutes reviewing and adding some new on Tuesday and then moving into the |
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57:22 | and function of the cns. All , thank you very much. And |
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57:25 | gonna stop the recording and and the here to make sure that I clear |
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57:30 | room on time, Have a good . Everybody remember that. A a |
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57:38 | all happy hour. Don't dis inhibit |
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