| 00:00 | Okay so what we discussed is the bunch of line um and we discussed |
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| 00:07 | bunch of line and toxin um uh targets the protein protein complex and this |
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| 00:19 | by targeting the fusion of the vesicular to the membrane protein. It prevents |
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| 00:26 | exocet ketosis and neurotransmitter release. And we discussed that there are different substances |
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| 00:34 | different um animals produced by bacteria produced microorganisms are found in their venom and |
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| 00:45 | produced by humans organophosphates that can target only the vesicular release of acetylcholine liam |
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| 00:52 | also the boston advocacy. So cold or the activity that happens the breakdown |
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| 01:01 | aceto Colin in the synaptic cleft. we stopped uh these two slides where |
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| 01:08 | discussed the excitatory Boston optic potential and really compared it to the employee potential |
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| 01:14 | you recall we said that employee potential is found that the neuromuscular junction in |
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| 01:20 | the skeletal muscle. Um uh we that this employee potential is a very |
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| 01:27 | deep polarization of about 70 mill involves this very large deep polarization will always |
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| 01:33 | up in the twitch of the We said that in the neuromuscular junction |
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| 01:38 | the civil Colleen is released in this junction it binds the acetylcholine receptors and |
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| 01:45 | there is a quantum of these acetylcholine molecules that will buy into these post |
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| 01:51 | receptors and these receptors are receptor So they're ligand gated channels and those |
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| 01:58 | will open and they will dip polarize plasma member of the muscle cell posson |
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| 02:05 | itself and will then deeper within these falls there are smart educated sodium channels |
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| 02:12 | those would be necessary to boost the phase of the action potential followed by |
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| 02:18 | of calcium. And we also talked is that this action with the control |
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| 02:23 | you see in the muscle Is much longer in duration than it is between |
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| 02:30 | . So the dynamics of this action duration is 10-15 to 20 times longer |
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| 02:37 | skeletal even in cardiac muscle cells. what we talked about is uh |
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| 02:46 | P. S. P. When neurotransmitter that is glutamate that is |
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| 02:50 | here and boston optic receptors for glutamate there ligand gated receptor channels and they |
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| 02:59 | open up one's glutamate as we see prison optically and binding of glutamate to |
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| 03:05 | glutamate receptor channels will allow an influx sodium. So you will have this |
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| 03:11 | polarization which is referred to as P. S. P. And |
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| 03:16 | stands for excitatory post synaptic potential. so these are transparent gated ion |
|
| 03:23 | But this instead of looking at the junction here, we're looking at neuronal |
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| 03:31 | . And unlike employee potentials that are 70 million balls or so in |
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| 03:38 | E. P. S. S. Are graded potentials. They |
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| 03:41 | in amplitude anywhere between behalf a mill excitation to all the way to the |
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| 03:49 | faction potential generation 20 to 30 million deep polarization and that all depends on |
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| 03:55 | number of the synapses that would be this past synaptic neuron from which you |
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| 04:00 | recording. So he's a greater So there are much smaller and there's |
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| 04:05 | consequence you need to engage at least or more excited to synapses in order |
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| 04:12 | de polarize this post synaptic cell So that would be adjacent synapses d |
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| 04:18 | to reach the threshold faction potential So glutamate binding to glutamate receptor channels |
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| 04:25 | cause deep polarization in the form of to passing out the potential. But |
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| 04:30 | the inhibitory synapses the release of gaba mu negatory kassid and binding of Gabba |
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| 04:37 | Gaba receptor channel will allow for influx fluoride. An influx of fluoride will |
|
| 04:43 | hyper polarization in the plasma number P. S fee is a greater |
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| 04:48 | polarization. The more synopsis are The larger the amplitude of the |
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| 04:55 | P. S. B. Is to be. I. DsB is |
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| 04:58 | same way the more inhibitory synapses are this past synaptic neuron. The larger |
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| 05:04 | graded this inhibitory personality potential will be of Gabba Gabba receptor channel. Also |
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| 05:11 | lot of influx of fluoride. And the influx of negative charge into the |
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| 05:16 | side of Seoul off neuron causes the hyper polarization of the plasma numbering in |
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| 05:23 | form of the inhibitory synaptic potential So we talked about how these channels |
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| 05:34 | ligand binds to these channels. And are of course subtypes of legitimate |
|
| 05:39 | And there are subtypes of Galba channels you learn. But what is demonstrated |
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| 05:44 | this particular diagram is binding of a to this receptor opens up the channel |
|
| 05:54 | channel. Okay, that same protein a receptor to login. It has |
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| 05:58 | binding side to the slogan and it's a channel. But there are metal |
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| 06:04 | signaling pathways in the brain. And which case we talked about when neurotransmitter |
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| 06:11 | to the receptor, that receptor is linked to G protein and G pro |
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| 06:19 | gets catalyst gets activated essentially and this protium can now affect nearby iron |
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| 06:28 | They can gate nearby ion channels. these are this type of signaling is |
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| 06:35 | or metabolic tropic in i on a signaling molecule binds to the receptor and |
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| 06:42 | receptor is also a channel whether it's her, it's a receptor is also |
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| 06:47 | channel or inhibitor. It's a receptor also a channel. But in medical |
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| 06:53 | signaling, binding of the neurotransmitter never up this particular protein but instead initiates |
|
| 07:01 | cascade of events through this G protein intracellular early that can effect and that |
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| 07:09 | open or even close nearby ion So these are G protein gated ion |
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| 07:16 | because they're gating or their key to to close them or to open them |
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| 07:24 | through G protean activation. Likewise, protein signaling can affect enzymes inside the |
|
| 07:32 | and set off secondary messenger cascades and can be affecting all different organelles inside |
|
| 07:41 | south, all the way down to nucleus of the cells. So depending |
|
| 07:50 | whether this neurotransmitter is I am a memorable tropic. The same neurotransmitter can |
|
| 07:56 | a different effect in the same cells two cells can actually co express ira |
|
| 08:03 | and metabolic tropic receptors. This has neurotransmitter different effects on different cells because |
|
| 08:11 | same neurotransmitter may exert a different Different cells have a different subset um |
|
| 08:19 | iona tropic or metal tropic channels that expressed and you'll see better understand this |
|
| 08:26 | . We talk about this diagram here particular. So this leads us back |
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| 08:34 | understanding the first discovered neurotransmitter molecule. by a synthesis degradation pathways locally. |
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| 08:43 | um salah Colin is of course was in your muscular junction is released by |
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| 08:50 | neurons. It's also in uh peripheral system and greedy. Angry on in |
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| 08:57 | pathetic. You're ons and of course a lot of acetylcholine in the brain |
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| 09:04 | expression of acetylcholine is not throughout the cortex or different structures in the brain |
|
| 09:10 | nuclear but rather confined to a few areas in the brain. So uh |
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| 09:18 | local name is synthesized on acetyl coa and Colleen come together and chat, |
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| 09:28 | or CH 80 is an abbreviation for to settle transfers. So silk. |
|
| 09:35 | and Colin shot on the Seattle Colin formed mrs Sydell Colin is now |
|
| 09:43 | Remember we said you need the secular . So they need to be transporters |
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| 09:48 | you need neurotransmitter present transporters will settle transporter will upload the bicycle with acetylcholine |
|
| 09:58 | . And then when acetylcholine is released there is excess psychosis, when there's |
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| 10:05 | of the vesicles to the membrane and of acetylcholine acetylcholine combined plus in optically |
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| 10:13 | the cns to both types of some that are ligand gated receptor channels |
|
| 10:21 | this is the iron, a tropic nick, acetylcholine receptor and some that |
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| 10:28 | G protein coupled and this blue and see it in subsequent slides. Also |
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| 10:34 | blue acetylcholine receptor is meta but tropical and a acetylcholine receptor to the kucinich |
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| 10:44 | receptor is going to be excited. and most currently receptors through the G |
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| 10:49 | coupled through the G protein coupled It can be inhibitory to the cells |
|
| 10:58 | that's referring to the previous slide where same substance acetylcholine can have two effects |
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| 11:06 | within the same neuron if that neuron co express nicotine nick and muscular receptors |
|
| 11:10 | can be like in a little tug against each other. Now when a |
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| 11:16 | colon is released into the snapping cloth is degraded. It is degraded by |
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| 11:23 | c local investor race is broken down cyclical industries into acetic acid and into |
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| 11:30 | and then coleene is transported back into pre synaptic terminals with sodium co transporter |
|
| 11:39 | Colin and Macedo co come together inside south they chat and your aceto Colin |
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| 11:45 | is made and it's uploaded and it through that cycle. So whenever there |
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| 11:49 | a demand for release or activation of ergic neurons release of acetylcholine acetylcholine. |
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| 11:59 | it binds to the receptors very the remaining molecules within the snap, |
|
| 12:03 | collapse will be broken down Now. I have here is a big |
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| 12:10 | It's a big cross red cross that medication for Alzheimer's and what does that |
|
| 12:19 | ? Well, most of the Alzheimer on the market, with the exception |
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| 12:25 | couple target a single Colin pathway. so it happens that Colin ergic signaling |
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| 12:33 | little Colin neurons die early in the onset of the Alzheimer's disease. And |
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| 12:41 | to prolong what is called by availability prolong the presence of acetylcholine in the |
|
| 12:51 | laugh. These medications are a citadel , nestor race inhibitors or calling mysteries |
|
| 13:01 | and some of the pharmaceutical commercials since rates inhibitors. Okay, since see |
|
| 13:08 | am. So most of the Alzheimer are satirical investor ace inhibitors. And |
|
| 13:16 | does that do? Well, if inhibit a seal colonel nestor is |
|
| 13:23 | that means you're not breaking down the Colin at the same rate and that |
|
| 13:31 | an opportunity for Seattle Colin that is remaining in Alzheimer's because it's pathology so |
|
| 13:38 | very little subtle Colin neurons are there's some that are still left, |
|
| 13:44 | lowest settle Colin tone if you And so to boost the stone, |
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| 13:51 | you can do is really just to the presence or the by availability the |
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| 13:59 | of the single column in the synoptic and hoping that the remaining acetylcholine neurons |
|
| 14:06 | synapses are still going to have a bit of the signaling faculty left active |
|
| 14:13 | functional. So when we talked about phosphates in this slide here and we |
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| 14:22 | organophosphates and they said a C. . E. Organophosphates like nerve gas |
|
| 14:27 | there also see local industries inhibitors? it goes back to our conversations that |
|
| 14:35 | depends how you prepare different substances and can use these different substances for um |
|
| 14:43 | reasons, medical reasons, for warfare . Uh And so nerve gases are |
|
| 14:54 | a cyclical industries inhibitors. Um And much of a single column can send |
|
| 15:04 | muscles into tetanus and can lock up diaphragm and can suffocate you. So |
|
| 15:12 | not an effect that will be felt nerve gases in the C. |
|
| 15:17 | S. But it's all of the and the motor neurons that release acetylcholine |
|
| 15:23 | will be affected. So now you the mechanism behind all farmers medications. |
|
| 15:31 | I told you it would be good you have like a page that you |
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| 15:35 | yourselves for Alzheimer's disease. So now can add additional information onto that page |
|
| 15:43 | that is that a zero Colin signaling impaired. That Colin ergic neurons are |
|
| 15:52 | and their neuro degenerating and that Alzheimer's , the main ones on the market |
|
| 16:01 | inhibit acetylcholine accessories and by inhibiting the industries, they increase the availability of |
|
| 16:08 | molecule and the remaining seed of Colin pathways. Okay, so this is |
|
| 16:16 | energy pharmacology, a suit of Colin nicotine receptor. And that receptor is |
|
| 16:24 | channel and it's called nicotine. It nicotine will also buying to this receptor |
|
| 16:34 | and it is going to open this channel just like a single colon was |
|
| 16:40 | to and therefore it is called an . So something that opens the channel |
|
| 16:46 | activates the channel, it's called an or a modulator. Something that closes |
|
| 16:53 | channel. Okay. Or impedes with opening of the channel is an |
|
| 17:02 | So nicotine and nicotine. Acetylcholine receptor its own agonist which is nicotine in |
|
| 17:10 | own antagonist which is cure ari uh sarinic receptor that should be here and |
|
| 17:18 | that with a g protein coupled It's a metaphor tropic receptor and it |
|
| 17:24 | has its own distinct agonist which is corinne an antagonist which is a |
|
| 17:30 | Okay, so there's a pharmacology, is the neuro pharmacology. This is |
|
| 17:38 | we can close and open these channels this is how you can manipulate nicotine |
|
| 17:45 | , I don't know, tropic direct versus most koranic interact metal tropic |
|
| 17:53 | Okay, we'll talk more about whatever signaling and some and some other |
|
| 18:00 | So let me uh pauses for a year and resuming the record in addition |
|
| 18:09 | the neurotransmitter systems and major neurotransmitters, acids, neurotransmitters and means and |
|
| 18:14 | We also talked about if you call . We also talked about 80 |
|
| 18:19 | and the Dennison and we also talked endocannabinoid. So if you are not |
|
| 18:25 | with any of this material somehow you those elections, you may want to |
|
| 18:28 | the video because it's a lot of interesting stuff that we've discussed now. |
|
| 18:33 | you recall, we talked about amino and these are glued remains and glutamate |
|
| 18:39 | Gaba and also lie scene acetylcholine and and cata cola means. Do you |
|
| 18:48 | what they fall under? They fall a means. Okay. And so |
|
| 18:54 | going to review these. So we about the means like a seagull |
|
| 18:59 | Now how do you identify these neurotransmitter in the brain or the body? |
|
| 19:06 | are two techniques that are quite common doing that. And we've alluded to |
|
| 19:10 | actually, one of them is artistic chemistry where you produce an antibody |
|
| 19:18 | that antibody is tagged with invisible marker that antibody is built against a specific |
|
| 19:29 | . So you can isolate a neurotransmitter one animal and you can inject it |
|
| 19:33 | another animal such as uh from rodents a rabbit and the rabbit will have |
|
| 19:43 | reaction immune reaction producing an antibody. you can isolate that antibody and tag |
|
| 19:49 | with a fluorescent marker. And then can have an antibody that is specific |
|
| 19:54 | a neurotransmitter candidate? let's say a company. And that can be applied |
|
| 20:02 | the tissue on the brain tissue. it can be applied on the entire |
|
| 20:07 | of a young or developing organism uh organism of course. And you can |
|
| 20:14 | the cells that have this specific So you apply this antibody with the |
|
| 20:24 | marker and only the cells. Only cells that will have this green square |
|
| 20:30 | is a neurotransmitter candidate will pick up bind to this antibody and will light |
|
| 20:36 | those cells. And so you can use immunity is the chemistry of course |
|
| 20:42 | a lot of pathology studies and understanding markers inside the south so how they're |
|
| 20:49 | molecules, how they're changing. You stay in very small uh molecules and |
|
| 20:57 | at the synapses and what these molecules inside the synapses. So this is |
|
| 21:03 | you know history chemistry you also have situ hybridization as another technique. And |
|
| 21:09 | the way the cells that don't have green your transmitter candidate will never light |
|
| 21:14 | under a microscope. So only the that have this candidate will get stained |
|
| 21:19 | will line up under a microscope and ones that don't have it. They |
|
| 21:23 | know. Okay another technique is when have a radioactively labelled probe with the |
|
| 21:33 | sequence of complementary cleric assets because this basically post genomic era and you can |
|
| 21:42 | sequences of neglect assets for start getting strands of M. RNA messenger RNA |
|
| 21:51 | and you will apply this radioactive label just like you would on the tissue |
|
| 21:57 | with the immunity as a chemistry with probe. Now we'll have to bind |
|
| 22:02 | in a complementary fashion to the Is trying to messenger RNA that might |
|
| 22:08 | expressing something like a protein or neurotransmitter neurotransmitter receptor and so on. So |
|
| 22:16 | can study neurotransmitter systems very well using techniques for staining um you know it's |
|
| 22:25 | chemistry and the central organization and this uh and consider hybridization, sagittal section |
|
| 22:33 | the whole embryo of a mouth showing distribution. So wherever you see dark |
|
| 22:41 | there would be higher densities of this gene of interest encoding truck be tyrus |
|
| 22:49 | be it's not really important that you that but you understand that you can |
|
| 22:54 | an aerial view of the entire aerial view of the neuronal surface and |
|
| 22:59 | hone in and the individual neurons that the south that specifically carrying neurotransmitters and |
|
| 23:06 | uh neurotransmitter receptors of interest. You also even go to the level of |
|
| 23:13 | molecules and single synapses and visualizing We also alluded to a technique that's |
|
| 23:19 | mini korean. We said that this what Uggla we actually did at the |
|
| 23:24 | isolated the fluid from one heart applied another heart and the applied fluid had |
|
| 23:32 | effect of slowing down the naive heart heart. So you can actually isolate |
|
| 23:40 | and you can apply these neurotransmitters through pipe pads and when you apply these |
|
| 23:45 | they should have an equivalent. The is if you were stimulating a pre |
|
| 23:50 | , if this is a glutamate in pie pad that you're applying here and |
|
| 23:54 | liquid, this uh response from this should be equivalent very stimulated. When |
|
| 24:00 | stimulating a little lethargic synapse, we axon that is projecting onto this post |
|
| 24:06 | neuron. So this is a neurotransmitter re or neuronal or synaptic mimic Re |
|
| 24:14 | you may. And if you had chance to look at the article that |
|
| 24:18 | alluded to in class about UNQ aging . This can be done in a |
|
| 24:24 | specific fashion at a level of single . Using on caging using lasers and |
|
| 24:32 | occasion the compounds that you can actually inside the chemical cages. And some |
|
| 24:37 | these compounds turn out to be neurotransmitters you can isolate and even ions that |
|
| 24:44 | can cage. And then by pointing laser through a microscope into one very |
|
| 24:49 | very small area, one single. now she can on cage glutamate. |
|
| 24:54 | this is important technique, laser microscopy on Cajun technique because if you imagine |
|
| 25:02 | neurons are surrounded by fluid and And so if you apply a drug |
|
| 25:07 | if you apply a neurotransmitter onto this . Then this synopsis that are located |
|
| 25:13 | close to This pipette will be activated so will be the nearby synapses to |
|
| 25:20 | lesser extent and more or less it follow the diffusion laws how well the |
|
| 25:25 | is going to diffuse in the surroundings how many analysis? Maybe five, |
|
| 25:31 | 10, maybe 20, maybe And with on occasion technique you can |
|
| 25:35 | specifically target just one area or one along the dumb drive, one single |
|
| 25:41 | spine. So I encourage you to at this material in the class supporting |
|
| 25:48 | So this slide again. But now look at it a little bit |
|
| 25:52 | Okay so we know I mean awesome . What is this? This is |
|
| 25:57 | us something about how they're being how glutamate is being synthesized and then |
|
| 26:03 | gamble is being synthesized. Whoa ! is a precursor to Gaba. So |
|
| 26:11 | major excited to a neurotransmitter is a to the major inhibitor neurotransmitter in the |
|
| 26:18 | . And all of the inhibitory So once it releases Gaba will contain |
|
| 26:25 | molecule, G. A. Or God, gamma butyric acid, |
|
| 26:35 | good atomic acid dicker boxers. Okay , vitamins, asset atomic acid dicker |
|
| 26:44 | list will turn it in together. come back to it in a |
|
| 26:48 | a civil coding. Great. We know this little Colleen and co and |
|
| 26:53 | need to chat to form a single . And then remember the molecule that |
|
| 26:59 | it down as the local in asteroids these are important molecules in the |
|
| 27:06 | Serotonin trip to fan needs Turkey has lot of trip to fan and relaxes |
|
| 27:16 | . It's a precursor for five hydroxy to Fan which is a precursor to |
|
| 27:22 | hydroxy Trip to me which is essentially molecule. And this is the synthesis |
|
| 27:31 | serotonin and no you will not be for serotonin and you will not be |
|
| 27:35 | for cata cola means. But this just to show you how some of |
|
| 27:40 | major molecules in the brain tire scene hydroxy this will turn tyrosine into die |
|
| 27:47 | phenyl Alamein which is dopa or Dopa dopa with amino acid dicker boxer |
|
| 27:57 | will turn into a dopamine dopamine, hydroxy Alice. So most of these |
|
| 28:03 | hydroxy analysis or decoder box analysis, hydroxyl, it or the dekalb |
|
| 28:08 | They they take the car back silly . You have dopamine and from dopamine |
|
| 28:15 | have norepinephrine, an epinephrine, more of the brain. And dopa or |
|
| 28:21 | . Dopa is a medication that is when there is dysfunction and dopamine signaling |
|
| 28:29 | there is lack of dopamine mints of medication and Parkinson's disease and old |
|
| 28:35 | So once again in this case you see that these neurotransmitter systems. As |
|
| 28:40 | mentioned previous lecture linked to different neurological . Dopamine will be linked to a |
|
| 28:48 | of motor diseases and dysfunction such as disease. And so dopamine or pharmacologically |
|
| 28:59 | dopa is a medication to help boost presence and production of dopamine. So |
|
| 29:06 | also. now learning about different not mechanisms of action but potential pharmacological strategies |
|
| 29:15 | will continue learning about them in the of you can block the substance that |
|
| 29:21 | something increased availability of that substance by is degrading enzyme here. You can |
|
| 29:31 | that if you supply a precursor which l dopa you will generate more dopamine |
|
| 29:38 | is effective. So you're not blocking instead boosting here, supplying something that's |
|
| 29:44 | the synthesis pathway rather than degradation on break Donald capital. Yeah this is |
|
| 29:53 | favorite group. I mean favorite slide . This is again a little bit |
|
| 29:57 | review of nicotine, egan rescreening Mhm. And this pathway is referred |
|
| 30:06 | a shortcut pathway uh When we talk metabolic trophic signaling and in this case |
|
| 30:13 | acetylcholine, sorry, binds to pseudo , mascara nick receptor uh finally you're |
|
| 30:23 | us that this much pain receptors meta and it's actually linked to g protein |
|
| 30:28 | . Yes it is. It will the data, it has different |
|
| 30:34 | alpha beta and gamma subunits and so of this data and gamma subunit following |
|
| 30:42 | binding of acetylcholine will then target nearby channels. Okay, what it can |
|
| 30:50 | is mustering across after binding of The muscular tonic receptor will activate a |
|
| 30:58 | podium and that you podium will open potassium channel. So what if you |
|
| 31:08 | the potassium channel potassium is going to the cell. What is going to |
|
| 31:13 | the outcome if the positive charge, now open potassium channel and positive potassium |
|
| 31:22 | leaving the sound, the cell numbering going to hyper polarized. So when |
|
| 31:30 | , nicotine or settle Kobe and bonds nicotine receptor. Okay, sodium well |
|
| 31:39 | inside. Well look at it in minute. But in most koranic receptors |
|
| 31:44 | have this situation where the mosque quranic , you will open the potassium channel |
|
| 31:51 | the hyper polarization and the shortcut pathway to the fact that there is no |
|
| 31:57 | intermedia is between the G pro dan the potassium channel. There's a binding |
|
| 32:04 | as you can see on the potassium to this, this gamma subunit of |
|
| 32:08 | G protein is going to attach and attaching to this channel it will change |
|
| 32:14 | confirmation of this channel and open channel allow for potassium to leave and hyper |
|
| 32:20 | neurons. What. Mhm. So and in general, what we have |
|
| 32:33 | realize is that neurons very intricately intertwined glial cells and not just for |
|
| 32:49 | not for just being a part of blood brain barrier. But this we'll |
|
| 32:54 | here is actually an astro site. what it shows here is another interesting |
|
| 33:01 | this reveals to you two. Very subject matters first of all, what |
|
| 33:06 | a tri apartheid synapse tri apartheid. , three parts neuron one you're on |
|
| 33:15 | and glia. And this is really is happening in the brain. The |
|
| 33:21 | a really tried apartheid. And the for it is following this example of |
|
| 33:27 | dermatologic signaling. So you have to is that takes glutamine and with the |
|
| 33:36 | line is it makes glutamate glutamine gets up into the vesicles. Glutamate gets |
|
| 33:42 | and then C. N. Glutamate will bind to iona trophic receptor |
|
| 33:49 | as well as metal but tried to with the leadership and I am a |
|
| 33:56 | . We remain fully staffed as well and de polarize the cells and meta |
|
| 34:02 | ligament receptors for the most part will an inhibitory effect on the south. |
|
| 34:10 | now you're seeing that this ying and of excitation and inhibition through the receptors |
|
| 34:18 | received the same molecule is a continuous as you talk about civil Colleen as |
|
| 34:24 | talk about luda mae but as you about Gaba is going to be a |
|
| 34:32 | different. So this glutamate once it released it doesn't stay in the synoptic |
|
| 34:38 | very quickly gets transported a portion of . Okay gets transported into glia, |
|
| 34:46 | a portion of wood and men buddha gets transported into Brianna portion into |
|
| 34:53 | If it gets transported into neurons it re uploaded into the classical buddha made |
|
| 34:59 | then this fantastical, full of with and can get released into the synoptic |
|
| 35:05 | but they will get transported into glia the transported and agree to will undergo |
|
| 35:15 | slower synthesis cycle where with gluten incentive it will become. Do you |
|
| 35:25 | And that glutamine will then be given these glial cells back into neurons and |
|
| 35:33 | neurons will take this glutamine And turn with vitamins and energy 80 p. |
|
| 35:40 | glutamate. Whoa. So basically neuron take care of its own glutamate. |
|
| 35:50 | if neuron has glia and neurons has these tripartite synapses then part of the |
|
| 35:59 | , not only synthesis but cycling and availability is very much dependent about what |
|
| 36:07 | glia is going to do. so several important concepts. Tri apartheid |
|
| 36:16 | glutamate receptors ion a tropic metabolic tropic signaling not just your own. Oh |
|
| 36:23 | also glial Somalia plays a part in overall excitatory glutamate tone in the |
|
| 36:34 | And how much of the excitation neurons communicate between each other. Very |
|
| 36:45 | So this is the pathway for cata means. And if you think about |
|
| 36:51 | and Gaba as fast signaling excitation inhibition when you talk about a subtle Colin |
|
| 36:58 | you're thinking about certain particular aspects and in the brain, certain movements, |
|
| 37:05 | states of the brain. If you cata colony and cyrus scene dopa, |
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| 37:13 | , norepinephrine epinephrine cata cola means will follow the same cycle that will get |
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| 37:22 | except for cata colony. And they rely on medical tropic signaling and they |
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| 37:30 | get re up taken back through the co transporter we uploaded into the vesicles |
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| 37:36 | released again. And some uh popular uh an illicit drugs. Amphetamine and |
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| 37:48 | control the re uptake of cata cola . So Cata colony in plays a |
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| 37:55 | in movement accelerates movement because this is , norepinephrine, epinephrine, this is |
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| 38:02 | of the brain. So these are upwards of the brain if you may |
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| 38:08 | typically good mood when you have uh and you alert and you're attentive, |
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| 38:14 | attention. It's also of course involved many other things like visceral functions in |
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| 38:19 | body. So don't forget that these are not only in the CNS but |
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| 38:24 | throughout the body and the periphery and the overall oh my prosthesis and overall |
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| 38:30 | of the brain and the body. so what is blocking up the re |
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| 38:36 | ? Does it prolongs uh they buy , availability of category and names and |
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| 38:43 | enough enough enough friends. So the , everything is movement is faster uh |
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| 38:51 | attention, blah blah blah. Uh of course quite dangerous and addictive drugs |
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| 38:59 | and illicit uh with uh um very when you're talking about anything that may |
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| 39:12 | synthesized because we have uh covid 19 we also have an epidemic of opiates |
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| 39:21 | we have an epidemic of fentaNYL and of these other things out there that |
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| 39:30 | go through labs that takes synthesis that like chemicals like imagine some crusty guys |
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| 39:37 | place mixing off some stuff and isolating and some tropical forest flies around and |
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| 39:54 | of the stuff that gets important. illegal comes through from china, eastern |
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| 40:01 | . A lot of it comes its through south America. A lot of |
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| 40:05 | manufactured cocaine is manufactured but at the time for some indigenous cultures uh use |
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| 40:15 | the plant of the cocoa plant. a little different from what has become |
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| 40:22 | drug trade of cocaine substance. So don't know what's going on with serotonin |
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| 40:29 | , appetite. Sleep learning, love , bad moon, no appetite, |
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| 40:38 | sleep, no learning. So this the precursor of serotonin trip to fan |
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| 40:47 | nine from Thanksgiving, everybody gets relaxed happy if the turkey has a lot |
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| 40:54 | trip defending it. It's a precursor serotonin, serotonin will go through the |
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| 40:58 | cycling, it will get rehab taken . And some of the more popular |
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| 41:05 | medications as brand names such as PROzac they have heard would be a blocker |
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| 41:12 | the serotonin re uptake and now you're seeing a common theme in the pharmacological |
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| 41:19 | so you can block the re you can block the breakdown in the |
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| 41:24 | of a C. Locally in you manipulate the receptor trees. Maybe you |
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| 41:29 | boost it with substances that are all of these things, part of |
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| 41:34 | therapeutic strategies that can be employed and diseases that would have in this case |
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| 41:39 | ergic dysfunction, lack of serotonin and blocking the re uptake of certain and |
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| 41:46 | can increase availability of that in the cleft, making better mood and |
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| 41:54 | But you know it's interesting that a of not only natural substances not pharmaceutical |
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| 42:01 | , natural substances and natural behaviors can some of these bio synthetic site cycle |
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| 42:10 | and signaling in the brain, thereby the mood, the appetite, |
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| 42:17 | resource functions, sexual behavior and so . So G proteins. We already |
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| 42:23 | at the shortcut and the shortcut was if you activated uh must be nick |
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| 42:32 | that will target potassium channels. And is a and other another illustration of |
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| 42:40 | two molecules in this case we're looking norepinephrine, it's the same molecules are |
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| 42:47 | two receptors. One of them is beta receptor, another is inhibitory alpha |
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| 42:52 | receptor. So if there aren't enough bonds to the stimulatory receptor, It |
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| 42:58 | actually activate this enzyme, a dental and from Dennison triphosphate will increase the |
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| 43:06 | of cycling campy and increase the production protein kinase eight and protein kindness |
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| 43:13 | Is one of the kindness system. cell and the function of kindness is |
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| 43:17 | the south is to fuss for a and a lot of times when there |
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| 43:23 | presence of kindnesses and there's foster relations can modulate the function of nearby receptor |
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| 43:31 | and ion channels a lot of times prolonged opening of these channels but also |
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| 43:38 | functions. Now that same molecule, activates inhibitory α two receptor. This |
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| 43:47 | two receptor note is linked to a G protein. This is not really |
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| 43:55 | up here on the left but this a stimulatory G podium or Gs this |
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| 44:04 | two receptors inhibitory because it is linked an inhibitory G program or Gi complex |
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| 44:13 | the function of JI complex is to identical cyclades and reduce The production of |
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| 44:23 | campaign and reduce protein tiny say So is happening through secondary messengers exactly. |
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| 44:33 | is a secondary messenger controlling the amount protein kindness. A One of them |
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| 44:43 | pushing okay pushing to produce more second and more protein kindness A. |
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| 44:50 | K. It's excited her and another is pulling away the system from producing |
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| 44:56 | so it's called push pull mechanisms. is trying to stimulate the production of |
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| 45:02 | and P. M. P. . Another one has seen him really |
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| 45:10 | right as opposed to kindnesses. We have in the brain other molecules that |
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| 45:16 | called foster rotations. So if kindnesses poorly things which means they add a |
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| 45:22 | . O. For group uh hospital , defense for lead and there is |
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| 45:29 | intricate balance even cellular early inside the . The presence of the receptors where |
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| 45:37 | data alpha two receptors so located what you the local increases in I don't |
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| 45:43 | , cyclist supporting kindness and so It was all linked and there is |
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| 45:50 | logic in there and specificity to all these molecules and interactions. But this |
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| 45:56 | a great example of how molecules norepinephrine influence the secondary signaling In two different |
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| 46:05 | the outcome. So what is different I refer to you about these |
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| 46:13 | Norepinephrine system, serotonin system and other molecule city we have been discussing |
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| 46:22 | Well this is what I already mentioned you that these molecules like norepinephrine, |
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| 46:30 | serotonin, they're not expressed throughout the amino acids such as glutamate gaba. |
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| 46:36 | will do widely expressed throughout the brain brain stem and the spinal cord. |
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| 46:42 | . But these molecules nor not enough serotonin or if you but or if |
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| 46:50 | zoomed in here, there's even more . They are expressed in very specific |
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| 46:58 | in the brain in this particular case norepinephrine is expressed in local civilians or |
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| 47:05 | blue nucleus because when you cut it actually oxidizes on the south steak, |
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| 47:11 | blue shape that you can see. so these neurons will produce more up |
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| 47:18 | . And what are all of these ? All of these arrows are projections |
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| 47:22 | are going to come out of this . Local Sibelius again, nucleus is |
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| 47:27 | part of the brain or brain The cell said are responsible for the |
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| 47:34 | similar functions. In this case. synthesizes norepinephrine and they will project the |
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| 47:42 | out of local civilians throughout diffuses throughout cortex, cerebellum in the spinal |
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| 47:49 | So we refer to it as a systems because uh they project very diffuse |
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| 47:57 | throughout the cortical matter. Serotonin is by raffi nuclei. And so you |
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| 48:03 | the serotonin raffi nuclei here shown in that will send their outputs and send |
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| 48:10 | serotonin ergic Exxon all terminals essentially. what serotonin will be finals and diffused |
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| 48:16 | the cortex and throughout the brain And then you have raffi nuclei that |
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| 48:23 | shown him green and they will be most of the serotonin, a senator |
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| 48:29 | projections in serotonin um into the into spinal cord. Okay, but this |
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| 48:37 | for the C. N. Again these are very special center. |
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| 48:41 | nuclei that produced these norepinephrine and serotonin . If you zoomed in here you |
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| 48:48 | see a single going. So Macedo is produced by magnus, salal or |
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| 48:53 | forebrain and a seal colon signaling. these neurons are dying. It will |
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| 49:03 | affecting the forebrain regions but it will be affecting the regions to which acetylcholine |
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| 49:11 | are projecting which is showing that it's usually have widely through the brain throughout |
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| 49:17 | brain. Just like with other molecules be discussed. Okay, there's a |
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| 49:25 | Colin also shown here in green and nucleus and the brains town and that |
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| 49:32 | bad uncle upon team. And the dorsal to the mental nuclei that also |
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| 49:39 | locally in and send the projections to areas in the brain but also diffuser |
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| 49:45 | are really is here. Norepinephrine rafi for serotonin, dopamine, dental |
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| 49:53 | mental area and substantial Niagara would produce to borrow mammal, every nucleus will |
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| 50:00 | histamine. So there's other molecules here hypocrite in that we haven't talked about |
|
| 50:06 | example. But this gives you an of the difference between how the amino |
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| 50:16 | are expressed throughout. You'll find prominence . Um And then all right frontal |
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| 50:23 | , citadel cortex, hippocampus, parietal , temporal lobe and there will be |
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| 50:29 | expression of that glutamate and synthesis and between neurons and glia all throughout. |
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| 50:38 | the synthesis of these specific molecules and we're talking about is confined to these |
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| 50:47 | specific synthesizing nuclei and the projections projecting throughout the brain. Andrew cannabinoids |
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| 51:04 | the cannabinoids And in this slide in highlights two very important features. So |
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| 51:13 | we have talked about interrogate signaling, means that pre synaptic neuron releases |
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| 51:19 | glutamate or Gaba pa synaptic neuron Uh However, in the instances when |
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| 51:28 | talk about gases such as nitrous oxide carbon monoxide or when we talk about |
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| 51:36 | , cannabinoid molecules produced endogenous lee by cells and most of the sauce in |
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| 51:43 | brain and the body. Once there heightened levels of activity there's going to |
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| 51:50 | a lot of release of either glutamate Gaba when there's going to be the |
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| 51:59 | of these neurotransmitters plus synaptic multi. going to be influx of calcium, |
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| 52:05 | channels an activation of the enzymes that start synthesizing into cannabinoid molecules and these |
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| 52:15 | molecules just like gases nitrous oxide and monoxide, they get synthesized and they |
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| 52:23 | freely traverse through the membrane so lipid and just like gases they will travel |
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| 52:32 | lee And mind to cannabinoid receptors that located present not frequently. So this |
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| 52:39 | receptors CB one who cannabinoid receptor one the function of cannabinoid receptor is that |
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| 52:46 | is g protein coupled receptor. So activating CB one receptor by releasing under |
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| 52:54 | under cannabinoids retro greatly activating CB they close voltage gated calcium channels through |
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| 53:04 | g protium signaling. It's a metal tropic reception. So what happens if |
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| 53:09 | closely synoptic voltage gated calcium travels? is no neural transmission. Remember that |
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| 53:19 | of calcium is one of the necessary because influx of calcium will allow for |
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| 53:26 | vest ical to fuse with the plasma and for the neurotransmitter release. So |
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| 53:34 | blocking calcium channel there is no calcium and you regulate the release of neurotransmitters |
|
| 53:42 | this is what endocannabinoid do the mechanisms endocannabinoid actions in the cns is to |
|
| 53:49 | the release of both excited to glutamate in the prohibitory Gava. And when |
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| 53:58 | talk we have a whole lecture on endocannabinoid system and medical cannabinoids, You |
|
| 54:06 | that CB one receptors, only one , their CB two receptors and CB |
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| 54:12 | receptors are predominantly expressed in glia and two receptors are dominant in michael blair |
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| 54:24 | as you know, michael lee is with inflammation repair and pro inflammatory cytokine |
|
| 54:34 | . So and the cannabinoids such as and a mind or to a record |
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| 54:40 | Glycerol to a G. They'll get by the body. They will target |
|
| 54:45 | one receptors on neurons and they will fast neural transmission, both excited to |
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| 54:52 | inhibitory balancing excited to inhibitory neural And we'll target CB two receptors that |
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| 55:00 | not shown here in glia that will concerned with slower processes such as inflammatory |
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| 55:07 | such as the reactions to injury and . Delta nine THC. Tetrahydrocannabinol is |
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| 55:20 | fatal cannabinoid. That means it is in the plant. And you will |
|
| 55:27 | so smart by the end of this that you will realize that cannabis plant |
|
| 55:34 | be annoyed concerned Canada's plant also derogatorily marijuana plant. That marijuana plants doesn't |
|
| 55:44 | produce delta nine THC. That it an acidic form of delta nine THC |
|
| 55:52 | delta nine THC A It actually has synthesis to synthesize THC A. Doesn't |
|
| 55:59 | THC. You'll be like, oh , so the cannabis plant has actually |
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| 56:06 | even have THC just as THC a nine is the location of the |
|
| 56:14 | Now it's carbon and you will be by in town. You'll see the |
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| 56:20 | stations and you'll see the centers and and Vape shops. Delta eight THC |
|
| 56:28 | here. So let me jump ahead this lecture that is coming in another |
|
| 56:36 | or so. I'll tell you that eight THC is not even produced by |
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| 56:42 | plant period DELTA eight THC is converted , it's converted. Okay. And |
|
| 56:57 | not a good way of doing it the lab. It's synthetic essential or |
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| 57:02 | synthetic because it's using a natural precursor . and with that there are many |
|
| 57:09 | implications. Delta eight ft see although see it as being on the |
|
| 57:14 | it is non regulated, there's a of unknowns. And in general stay |
|
| 57:21 | from synthetic cannabinoids, synthetic cannabinoids, cannabis, synthetic marijuana has nothing to |
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| 57:29 | with the plant, has nothing to with phyto cannabinoids. It would be |
|
| 57:34 | and deadly synthetic phenomenal is um so even is a semi synthetic cannabinoid |
|
| 57:43 | it's not a semi synthetic because it not born from two chemicals coming together |
|
| 57:48 | the lives of scientists mixing it up saying here it is, but rather |
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| 57:53 | taking a natural precursor, Putting that chemicals mixing it out, heating whatever |
|
| 57:59 | saying now we have delta eight that not regulated. And so this is |
|
| 58:05 | I'm getting ahead of myself for a reason. Uh deep polarization induced suppression |
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| 58:12 | inhibition. What does that mean? polarization induced suppression of excitation when uh |
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| 58:18 | neuronal signaling was discovered within the Where and the cannabinoids director greatly will |
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| 58:25 | and pre synaptic cannabinoid receptors and will the release in particular of Galba of |
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| 58:32 | neurons. So at first it was wow, it stops the release of |
|
| 58:37 | . It must be making people crazy of course people looked a neuroscientist like |
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| 58:43 | THC delta eight THC. Tetro phenomenal hydro phenomenal does in the brain cannabinoid |
|
| 58:51 | THC by binding to CB one receptors not only balance gaba and glutamate excitation |
|
| 58:58 | is also responsible for the euphoria effect the so called high effect. Okay |
|
| 59:04 | activation of CB one receptors are responsible this effect. But these kind of |
|
| 59:11 | by the cannabinoids and buy phyto cannabinoids phyto cannabinoids they bind to CB one |
|
| 59:18 | , they mimic the activity of the cannabinoids and they bind to CB one |
|
| 59:24 | . And endocannabinoid phyto cannabinoids. Cannabinoid is applicable to both excitatory and inhibitory |
|
| 59:35 | . So there's a lot of deep . It is a lot of |
|
| 59:40 | Then cannabinoids will suppress inhibition. There's lot of deep polarization and excitatory |
|
| 59:46 | There's a lot of glutamate release. a lot of excitation. An endocannabinoid |
|
| 59:52 | suppress this excitation and that's why it's to as deep polarization induced suppression of |
|
| 59:58 | ambition. Deep polarization induced suppression of in reality when there is heightened levels |
|
| 60:04 | activity and too much activity. Cannabinoid kicks in and balances out the gaba |
|
| 60:10 | glutamate release. So this is very and the synthesis of under cannabinoids and |
|
| 60:18 | function of under cannabinoids and the brain the body is vast will cover some |
|
| 60:24 | it um but then the cannabinoids are very much involved in paying mediation in |
|
| 60:33 | of other processes and thermal regulation and overall of the body and the |
|
| 60:43 | Okay, so, amino acid new transmitters, glutamate. Listen, gabba |
|
| 60:49 | , we know it all glutamate. , the atomic acidic or box |
|
| 60:54 | This is God. God will take deter box. Elation means you are |
|
| 60:59 | this for boxing group off. so you have a blue dynamic acid |
|
| 61:04 | is good. Um it's an acid you take the Citigroup off when you |
|
| 61:09 | it into Gaba. So once all of the inhibitor into neurons that |
|
| 61:13 | Gaba, inhibit their neurotransmitter will have ends on God. And so you |
|
| 61:18 | use immunity chemistry or other means of for God. And all of the |
|
| 61:24 | that will show positive for God will inhibitory interneuron, wow, this is |
|
| 61:30 | cool. We're making a lot of . And so Okay, so is |
|
| 61:35 | cycling with glutamate transporters into into neurons unique to glutamate. Now, it's |
|
| 61:42 | happening together And also uh glial cells be involved in regulation on this. |
|
| 61:50 | . And you have again, transporters transport Gavin glutamate into the south and |
|
| 61:55 | have transporters that transport the secular gamma into the gamma vesicles and the secular |
|
| 62:03 | transporter into the glutamine festivals. All , so, we're going to stop |
|
| 62:10 | today, appreciate everyone on a short , being on zoom, apologize for |
|
| 62:17 | being able to be in person. be there on monday for sure. |
|
| 62:20 | just didn't want to. We're on , 20 minutes late and lose everyone |
|
| 62:26 | I may have lost some of you the first five minutes. Or if |
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| 62:29 | didn't read my email early enough. any case, this lecture is recorded |
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| 62:34 | deposit recording here and when we come , we'll build into greater detail into |
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| 62:40 | dramaturgical glutamate neuro pharmacology. I am tropic Alpine India kind of as well |
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| 62:46 | the metal with tropical We have made and you will know a lot about |
|
| 62:53 | and gaba signaling, acetylcholine signaling what molecules do in the brain, what |
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| 62:58 | functions are and what diseases there uh or dysfunctions are associated |
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