| 00:02 | So this is lecture five of cellular . And we're actually looking at the |
|
| 00:10 | that is labeled lecture four neurotransmission. gonna go over this fairly fast. |
|
| 00:19 | because a lot of you are familiar this. And I'm also uh thinking |
|
| 00:27 | uh it will be some of these that will repeat in the next few |
|
| 00:32 | and maybe throughout the course altogether. what we know about major neurotransmitters, |
|
| 00:40 | neurotransmitter systems, really what they are that we have major classes. We |
|
| 00:46 | amino acids. Those are gamma glycine glutamate is the major excitatory neurotransmitter |
|
| 00:55 | the C MS gamma and glycine are major inhibitory neurotransmitters. C MS, |
|
| 01:03 | are acetylcholine, dopamine, epinephrine, , norepinephrine and serotonin. And we're |
|
| 01:12 | look at function of those uh maybe lecture, starting next lecture. And |
|
| 01:19 | there are peptides that also serve essentially neurotransmitters. So CCK and Cephalin neuropeptide |
|
| 01:29 | substance P. Um Now there are non classical, we would call them |
|
| 01:38 | because they were not really talked about about 2030 years ago, maybe. |
|
| 01:46 | adenosine, which is the core of triphosphate molecule A TP uh is a |
|
| 01:54 | So remember we talked about how att get released and A TP can bind |
|
| 02:02 | the astrocytes. And astrocytes have these two Y receptors for A TP. |
|
| 02:10 | it can influence astrocyte cellular processes, metabolism uh production of glutamates and such |
|
| 02:18 | we discussed gasses. So, nitrous and carbon monoxide co and L lipid |
|
| 02:26 | molecules and the cannabinoids. So those molecules that are generated inside our cells |
|
| 02:33 | they are soluble just like gasses are to lipids as well. So, |
|
| 02:41 | soluble are also gasses. That means they pass through the membranes and endocannabinoid |
|
| 02:47 | through the membranes and they're not stored the vesicles and released in the |
|
| 02:52 | Unlike your major neurotransmitters here or uh dennison and a TP which sometimes we |
|
| 03:01 | they are released in vesicles but don't , I don't think all of it |
|
| 03:05 | add. So what is the difference these amino acids? And it means |
|
| 03:12 | is gonna be the focus in this . The difference is that amino acids |
|
| 03:18 | are illustrated here. I wonder if can raise this screen skin control. |
|
| 03:54 | I'm not gonna worry about it. gonna just draw. So the major |
|
| 04:00 | to start thinking about is first of , there are billions of cells that |
|
| 04:09 | Java or glutamate throughout the brain. if you were to look in the |
|
| 04:16 | , it's a sort of a, cartoon representation of the brain. If |
|
| 04:20 | were to look, you will see these amino acid expressing cells that we're |
|
| 04:25 | about. Billions are expressed everywhere throughout C MS. So balance. So |
|
| 04:41 | is the amino acids and what's different amino acids and amines is that amines |
|
| 04:48 | as in this case, acetylcholine or . But it's also applicable to epinephrine |
|
| 04:56 | serotonin that we'll study is that there's a small number of cells in hundreds |
|
| 05:03 | thousands, only in the specific Gracey Coline. It's this p of |
|
| 05:10 | a encephalon complex and another nucleus media nucleus, these are two small areas |
|
| 05:19 | will produce a PSE coline that will the CNS and quite often also have |
|
| 05:28 | into the periphery also. So these very limited in number, they're very |
|
| 05:34 | where those molecules are synthesized. But projections from these nuclei are very diffused |
|
| 05:42 | quite broad. And uh some of are broader. In this case, |
|
| 05:47 | see the cole for example, compared the plea broad projections of dopamine, |
|
| 05:52 | called diffuse because they're quite complex. don't understand really their complete structure. |
|
| 06:00 | uh how this what we call the system of amino uh amine neurotransmitters works |
|
| 06:08 | the brain. Uh But this is example of acetylcholine and dopamine and it |
|
| 06:14 | to other amine neurotransmitters also chemical synopsis we talked about, most of them |
|
| 06:21 | between axons and dendrites. But there always exceptions. So you can have |
|
| 06:27 | synopsis, even dendrodendritic even some of synopsis. Um some of the |
|
| 06:36 | uh some of the dendrites um are some of the axon to dendrites spine |
|
| 06:44 | is Axo spinous versus to actual Uh dendrite to dendrite is dendrodendritic. |
|
| 06:50 | all of these different variations now the that project onto the dendrites and |
|
| 06:57 | they can influence how the cell thinks the integrated properties of the cell, |
|
| 07:02 | cells that projects a sonic projection. to act honestly can't really influence how |
|
| 07:09 | cell decides whether it wants to fire action potential or not. The cell |
|
| 07:14 | whether to fire an action potential that of these evidences in the SOMA produce |
|
| 07:18 | action here, sends it down the . Therefore, this Axio so cops |
|
| 07:24 | only influences what we call modulate the of the cell. Not that with |
|
| 07:30 | cell integrates but only the output of cell, the form of the action |
|
| 07:36 | . And these determine and influence how cell will integrate. That information gap |
|
| 07:44 | is another type of synapse that we . These are electrical junctions and I'm |
|
| 07:49 | speak about them at great length, they will come back when we talk |
|
| 07:54 | neurological disorders. And later in the gap junctions are electrical junction. So |
|
| 08:00 | you have an action potential or an change or chemical change in one of |
|
| 08:06 | sides of the south, and that without any delay is going to spread |
|
| 08:12 | the adjacent neuron if there is a junction. So typical synoptic space between |
|
| 08:21 | here is about chemical synopsis is about nanometers in space between the two |
|
| 08:29 | It's called the synaptic cleft and gab narrowed down to about four nanometers in |
|
| 08:37 | . You essentially have two membranes of two cells coming very close together that |
|
| 08:44 | connection and each side uh connections that connect on the two connections then form |
|
| 08:51 | single gap conn. And these uh are called electrically coupled ions can flow |
|
| 09:03 | these gab junctions but also small molecules small messengers like cyclic A and |
|
| 09:10 | for example, a secondary messenger can between these uh electrical synopsis. Uh |
|
| 09:20 | says, unlike most chemical synopsis, synopsis are bidirectional. So when we |
|
| 09:27 | about chemical synaptic transmission, we think it comes from pre synoptic side and |
|
| 09:32 | to pos synoptic side. But we know that there are auto receptors on |
|
| 09:37 | pre synoptic side. So that signaling also be retrograde in the way. |
|
| 09:42 | we also know that endocannabinoid signal retrograde the gasses also and LC signal |
|
| 09:50 | So although it's still thought that more a directionality, pre synoptic to postsynaptic |
|
| 09:56 | more bidirectional in these go junctions, lot of things can cross from one |
|
| 10:04 | into the other very easily. It's important for very fast transmission of |
|
| 10:11 | So when there is a synaptic neurotransmitter , when this release happens here, |
|
| 10:20 | say this has infused but this vesicle and released its its content and it's |
|
| 10:27 | going to bind to poynt receptors. , binding of this molecule to posy |
|
| 10:36 | and then seeing some sort of a posy apply this time period for the |
|
| 10:44 | to cross the synapse to bind to receptor and to change the potential across |
|
| 10:50 | membrane. Here, this will take five, maybe sometimes even 15 |
|
| 10:59 | And this is what is called synaptic . And this sort of a delay |
|
| 11:08 | not exist in the gap junctions. these synopsis in a way are slower |
|
| 11:17 | the gag options. Uh gap junctions important for integrating po synoptic potentials that |
|
| 11:26 | occurring simultaneously for very fast transmission and for synchrony in neuronal networks. So |
|
| 11:34 | is an example of a network that receiving input and is receiving input from |
|
| 11:43 | side, let's say from cell one it's both cells are receiving input at |
|
| 11:50 | same time. And they actually synchronize if one cell receives the input, |
|
| 11:55 | second cell is also going to So this is with gout junctions, |
|
| 12:00 | can see that action potentials get produced the same time. And if you |
|
| 12:06 | gout junctions and those cells are still inputs from the network, but now |
|
| 12:13 | spiking it very different sequences in So they're no longer as synchronized. |
|
| 12:23 | this gap junction connectivity is very important synchronizing activity of neurons and neuronal networks |
|
| 12:31 | for fast transmission of that activity through networks as well and supporting this very |
|
| 12:40 | activity that doesn't have delays, like would see in the synaptic transmission. |
|
| 12:47 | , neurotransmitters, they need to be , they need to be stored in |
|
| 12:52 | synoptic terminals. Uh they are released optically if you isolate glutamate or Gaba |
|
| 13:02 | any other one of the amine neurotransmitters we're talking about and you apply it |
|
| 13:07 | a cell that has receptors for glutamate or amine neurotransmitters. You should have |
|
| 13:13 | postsynaptic response. Uh CNS contains diverse of synopsis that use different neurotransmitters. |
|
| 13:21 | brain slice is quite often as a and this is how we learned a |
|
| 13:27 | about neurotransmission, especially uh when we about quantum release of neurotransmitter, something |
|
| 13:34 | we'll discuss in a few slides in , we s we keep these slices |
|
| 13:40 | for a while and we can measure transmission and measure the efficacy of it |
|
| 13:46 | do plasticity studies that we talk later this course, long term depression, |
|
| 13:51 | term potentiation studies, spy timing dependent and and others. And there as |
|
| 13:58 | late, there are new methods for synoptic transmission with optogenetics where light sensitive |
|
| 14:08 | are essentially controlling a change of membrane . But all of these components from |
|
| 14:19 | synoptic synoptic side is what we refer as neurotransmitter system, synthesize transport release |
|
| 14:29 | degradated enzymes. There's transformers of neurotransmitters into the preoptic side and postsynaptic |
|
| 14:36 | you have ion channels, go coupled , downstream cellular and secondary messenger cascades |
|
| 14:43 | this chemical synaptic activation. In order the synaptic transmission to occur, there |
|
| 14:52 | to be an action potential that arrives the external terminal. So if this |
|
| 14:59 | the axon here, OK, it's long axon recall. It has myelin |
|
| 15:06 | wrapped around it and it has no run beer and it goes, it |
|
| 15:12 | , it goes until it gets Then you have the D drive is |
|
| 15:17 | . It looks kind of a funky . Uh This is a neuron right |
|
| 15:22 | . This is a cell with its , branches and so on and basal |
|
| 15:30 | . So the axon initial segment, area here is what's going to produce |
|
| 15:35 | action potential and this action potential will regenerated at each node of Rovere and |
|
| 15:45 | it's going to reach the external So in order for synaptic transmission to |
|
| 15:50 | place, you need action credentials. this is a quick refresher of the |
|
| 15:55 | potentials that typically cell is sitting at is called resting membrane potential R and |
|
| 16:04 | of about minus 65 millivolts. It mean that the number and potential nothing |
|
| 16:10 | fixed in a straight line in So this resting number and potential uh |
|
| 16:17 | I'm gonna run out of space with these chairs here, draw a little |
|
| 16:26 | here which you already have. So resting number and potential of minus 65 |
|
| 16:33 | . It's not something that's going to set, it's going to fluctuate all |
|
| 16:38 | time. It's gonna be a little more depolarizing coming closer toward the threshold |
|
| 16:46 | action potential. So this is the value for action potentials. It's always |
|
| 16:52 | be fluctuating around this value. If goes this direction, it's getting depolarized |
|
| 16:58 | plasma membrane. If it goes from membrane potential to more negative values, |
|
| 17:04 | gets hyper polarized. The actual potential initiated here and is produced by voltage |
|
| 17:15 | sodium channels and voltage gated potassium And during the initial depolarization of the |
|
| 17:25 | has enough of the inputs coming in , enough of the positive inputs coming |
|
| 17:31 | other synopsis into this neuron. This is going to get depolarized and it's |
|
| 17:40 | to open the sodium channels. These voltage gated channels. Remember. So |
|
| 17:45 | sodium and dain channels of voltage gated , it's gonna open sodium voltage gated |
|
| 17:51 | . It's gonna cause influx of sodium it's going to depolarize the south. |
|
| 17:58 | is a duration of a little bit than a few milliseconds. It's going |
|
| 18:05 | depolarize the plasma membrane which is BM the voltage of the membrane measured in |
|
| 18:15 | . It's going to pass the zero , it's going to pass a zero |
|
| 18:22 | . It is called overshoot. It's to overshoot the zero line at which |
|
| 18:28 | there is more dilation, more sodium , more dilation, more sodium |
|
| 18:35 | But sodium channels have a certain That means they open for a short |
|
| 18:40 | period and then they close and then channels open up and they're responsible for |
|
| 18:46 | falling phase of the action potential. quite often will drive it below the |
|
| 18:51 | number and potential of this under shoot then will re polarize it with the |
|
| 18:58 | of sodium and potassium pumps. So ions will flux down their concentration |
|
| 19:06 | There's a lot of sodium fluoride on outside of the cell, it is |
|
| 19:10 | to go in, there's a lot potassium on the inside of the |
|
| 19:13 | it's going to go out and then little bit the slower fashion. So |
|
| 19:18 | gated. So, so the potassium are vast, the pumps are slower |
|
| 19:24 | they don't conduct as many ions, they will eventually restore this unequal |
|
| 19:30 | what we call a charge, a of sodium fluoride on the outside and |
|
| 19:34 | lot of potassium on the inside. this time when you have the action |
|
| 19:43 | , you have what is called absolute period. And during this time |
|
| 19:47 | it doesn't matter if the cell receives synaptic inputs, more into polarization, |
|
| 19:52 | cannot have another action potential writing on of this one. But during the |
|
| 19:57 | period, during this repolarization phase, soon as it crosses back as this |
|
| 20:04 | line, which is the threshold for potential from that point on if there |
|
| 20:10 | a strong input coming into the it could or is it another active |
|
| 20:15 | ? That's why it's referred to as refractory period. So, absolute versus |
|
| 20:23 | , there's more information here that uh may not be familiar with like equilibrium |
|
| 20:29 | or driving force, but we're gonna it out for the sake of of |
|
| 20:34 | course. Uh And as long as could follow what I was just |
|
| 20:39 | then you're in good shape. So order to release these neurotransmitters, we |
|
| 20:45 | action potentials. The major amino acid transmitters, glutamate glycine gaba glutamic acid |
|
| 20:55 | . So, Gad is a key in Gaba synthesis. Gab allergic neurons |
|
| 21:04 | a major source of synaptic inhibition in CNS. And you can see that |
|
| 21:12 | as this carboxyl group. And if decarboxylate glutamate, you have GVA. |
|
| 21:17 | that's why you have gam acid It means the inhibitory cells will all |
|
| 21:23 | gap, they will all be expressed gap. And if you recall these |
|
| 21:31 | when we talk about, you give it to ourselves, we typically |
|
| 21:35 | to inter neurons that are living here the projection cells. So these are |
|
| 21:46 | projection cells that innervates other networks and are inhibitory interneurons and they are local |
|
| 21:59 | . So typically would be capital. are exceptions in the sense that some |
|
| 22:07 | neurons may have uh longer axons and of the excitatory cells may not have |
|
| 22:13 | going into the adjacent networks. So there's exceptions to, to these |
|
| 22:20 | but these are the three major And so all of the inhibitor into |
|
| 22:26 | , all of the neurons that release , they will stain. It's a |
|
| 22:33 | marker. God is a good marker all of the Gava cells. If |
|
| 22:40 | were to apply God, stay Y you uh uh por boxy witham |
|
| 22:49 | box. If you apply on the and all of the sauce that express |
|
| 22:55 | and release Gaba Glow will show up then the cells that are excited to |
|
| 23:04 | , they will not show any positive but excited her here positive, but |
|
| 23:12 | excited for it. All right. , neurotransmitter receptors, once you release |
|
| 23:18 | neurotransmitter, postsynaptic glutamate will bind to receptors and cause an EPS. Pe |
|
| 23:27 | stands for excitatory postsynaptic potential epsc just be nice. I'm gonna try to |
|
| 23:45 | it here and for people in class be able to see it later. |
|
| 23:58 | if the excited during mir transmitter is , Luda oath, the effect is |
|
| 24:11 | lost synaptic potential eese if Gaba is and it binds to Gava receptors that's |
|
| 24:36 | to produce and inhibit sorry fast. that potential or I D S |
|
| 24:54 | So this is glutamate glutamate receptors, receptors in order to generate EDP, |
|
| 25:03 | gonna be influx, it's a So there's gonna be an influx of |
|
| 25:10 | and also calcium through glutamate receptors. order to hyperpolarize the cells, Gava |
|
| 25:19 | channels when they open, they will for the conductance of chloride to negative |
|
| 25:25 | is gonna cause the hyper polarization. , there's two things that need to |
|
| 25:35 | . Pre cynical, you need action and you need calcium influx. So |
|
| 25:42 | the action potential arrives in this pre terminal, there's going to be calcium |
|
| 25:47 | . Calcium is necessary for this vesicle complex to fuse with a membrane protein |
|
| 25:56 | . So that the fusion can take between the vicar membrane and neuronal |
|
| 26:03 | And you have exocytosis following exocytosis. vesicle gets recycled endocytosis back into the |
|
| 26:11 | on a terminal. It gets refilled neurotransmitter again. So this is the |
|
| 26:20 | of exocytosis. So you need calcium salt to their confirmation once they get |
|
| 26:26 | by calcium, therefore, they can and form protein protein complex vesicle membrane |
|
| 26:33 | with pre synoptic membrane neurotransmitter received in cleft, received, released in the |
|
| 26:40 | and vesicle membrane recovered by endocytosis. of these things happen every time there's |
|
| 26:47 | fusion, vesicular release. In some , neurons can produce partial fusion in |
|
| 26:58 | instances when there's significant depolarization that will a full fusion and the vesicle will |
|
| 27:04 | endocytosis and will get coated by Claritin reprocessed, acidified with H plus, |
|
| 27:14 | with neurotransmitter and again, placed close the zones of the release. In |
|
| 27:20 | instances, it will go back into early end of zone and will get |
|
| 27:25 | all together into a new vesicle for . As we talked about already. |
|
| 27:33 | have a tripartite synapse as we saw the images before glutamate release. Once |
|
| 27:41 | gets released, it combines to io glutamate receptor channel. So, metabotropic |
|
| 27:47 | receptors and then that glutamate gets, cycled back and will have glutamate neuronal |
|
| 27:55 | that will reupdate that glutamate. So of the neurotransmitters just linger around the |
|
| 28:01 | . In this club, they bind neurotransmitters and they get released uh to |
|
| 28:08 | receptors and they get unbound and they either degraded here and zooma degraded or |
|
| 28:14 | get transported back into the preoptic be loaded into the bicycles for the |
|
| 28:21 | release. But in many instances, actually all of the instances you have |
|
| 28:29 | transporters of glue as a visa leo transporters that will take glutamate pop will |
|
| 28:37 | it through the glutamate synthese for glutamine then give it back to neurons and |
|
| 28:43 | with glutamate will synthesize an energy glutamate reload these vesicles. So this shows |
|
| 28:50 | how leah these astrocytes are involved in the cycle of glutamate and they control |
|
| 29:01 | availability of glutamate between nerves. If an impairment in g leo glutamate |
|
| 29:12 | there can be too much glutamate and isn't gonna be as much of reuptake |
|
| 29:17 | only neurons will be react it And that can cause hyper excitability. |
|
| 29:24 | , if this function in gli can imbalance and make this synapse, for |
|
| 29:31 | , hyper excitable if it doesn't have proper transfer of glutamate back into glial |
|
| 29:40 | . Now, there are three major acid receptors that are ionotropic or there |
|
| 29:50 | channels and those are A and MD and Kate. And they're responsible for |
|
| 29:59 | Fastin tic transmission. They are sensitive voltage and liens or chemicals. They |
|
| 30:09 | flow of fairly large currents, especially an MD A receptor. And they |
|
| 30:15 | be selective to ions. Although they conduct like voltage gated sodium channels are |
|
| 30:22 | for sodium voltage gated potassium channels are for potassium. These glutamate receptor channels |
|
| 30:28 | be conducting multiple ions in and out this channel. They have their distinct |
|
| 30:38 | and NBA Kate and they also have distinct antagonists and a lot of other |
|
| 30:44 | . So we'll look later in this . These are the agonist is and |
|
| 30:49 | MD A for glutamate receptor and the antagonist for er CNQX. And for |
|
| 30:57 | MD A receptor is a PPAP VA five. I was raised to say |
|
| 31:03 | a PV and somebody else said it's P five. So I still say |
|
| 31:07 | PV because it was written like it was like that. It was |
|
| 31:18 | numeral five, but I kept calling A PD and many people did for |
|
| 31:24 | years. So Boston Synoptic to generate IP SPS, we're gonna talk about |
|
| 31:31 | once glutamate gets released alpha receptors open and alpha receptors are responsible for the |
|
| 31:40 | phase of the EPSB and an MD receptor. So this is our reyn |
|
| 31:48 | . Still we have glutamate that has released. Gamma will bind to A |
|
| 32:00 | an MD A receptors that are channels it is going to produce poop and |
|
| 32:10 | . And so the early phase, early component of this Epsp is due |
|
| 32:16 | ample receptors and the slave component of DS B is due to N MD |
|
| 32:26 | receptors. So amber receptors get activated and amper receptors and kate receptors are |
|
| 32:34 | to each other in kinetics and in . So that's why a lot of |
|
| 32:38 | they're grouped together Kate. Now, one testicle gets released, that vesicle |
|
| 32:52 | contain what we call a certain number a quanta of the neurotransmitter. And |
|
| 33:04 | can vary a little bit so that can be, you know, let's |
|
| 33:10 | , or acetyl colon and neuromuscular it can be 2000 to 4000 molecules |
|
| 33:17 | here. And you'll say that's a of variability. Yeah, it |
|
| 33:20 | but it's only twice. It's you know, 10 times variability in |
|
| 33:25 | , 20 versus 2000 or 100 times so on. So one neurotransmitter vesicle |
|
| 33:35 | and release will generate what we call , a unitary EPSP or miniature po |
|
| 33:47 | . And this miniature apo synoptic potential really small. It's typically about a |
|
| 33:54 | of about hun half a millivolt in . Now, it, so you're |
|
| 34:03 | and you're producing the CPSP. Now action potential arrives and now two arrive |
|
| 34:10 | the same time or very close to other. And now you have more |
|
| 34:15 | because now you have released two So if you stimulated the synapse, |
|
| 34:25 | fuse two vesicles, your epsb is be a multiple and the amplitude here |
|
| 34:36 | the second trace is going to be one millivolt. And that's because approximately |
|
| 34:43 | same number of neurotransmitters are contained in vesicle. And then if you release |
|
| 34:53 | vesicle neurotransmitters from the pre synoptic And again, it could be because |
|
| 34:59 | have three very fast action potentials that in, you have a lot more |
|
| 35:06 | and you're going to produce now, times the size of this miniature upsp |
|
| 35:13 | this, of this very unitary smallest that you see. Uh So maybe |
|
| 35:21 | is in your way a little bit . So now this is gonna be |
|
| 35:28 | third three synopses activated and this delta going to be about 1.5 millivolts. |
|
| 35:38 | there there are multiples of the miniature EPSP and resting number and potential is |
|
| 35:48 | minus 65 millivolts and the threshold for potential is about minus 45 mills. |
|
| 35:59 | that tells you that you need to a lot of synopsis or you have |
|
| 36:06 | release a lot of vesicles in order reach this threshold value for action potential |
|
| 36:16 | . So that's what we mean by analysis. So if you, for |
|
| 36:21 | , determine that your miniature is half millivolts and then you need to have |
|
| 36:28 | change of 30 millivolts. And here need at least 60 excitatory synopsis. |
|
| 36:38 | 60 of these excitatory synopsis that will come from one synapse for releasing all |
|
| 36:44 | these testicles of WS or multiple synopsis the same time. But this is |
|
| 36:50 | we can analyze what's miniature. What the larger responses that will drive the |
|
| 36:56 | past this threshold for action potential So once the uh glutamate is |
|
| 37:04 | it will bind and will open up but it will not open up an |
|
| 37:09 | A receptor. So, glutamate binding not enough because an MD A receptors |
|
| 37:13 | blocked by magnesium and they have to a depolarization. So the membrane has |
|
| 37:19 | get depolarized, maybe not necessarily all way to minus 30 millivolts, but |
|
| 37:25 | has to get depolarized first by which is responsible for the initial. |
|
| 37:31 | this has to be a depolarization And this depolarization, initial depolarization comes |
|
| 37:37 | ample receptor activation and only in the of this depolarization, this magnesium, |
|
| 37:44 | going to leave the channel and when leaves the channel and then the receptor |
|
| 37:51 | is open and it is going to sodium and calcium and also allow for |
|
| 37:57 | elu of potassium. Now, that's is important. So, sodium is |
|
| 38:03 | important uh depolarizing ion. Calcium does contribute that much to change in the |
|
| 38:09 | potential. With calcium contributes a lot the postsynaptic cellular signaling. It can |
|
| 38:16 | as a secondary messenger, it can with the kin AIS. So, |
|
| 38:22 | MD A receptor is both, it's and lend dependent. So it has |
|
| 38:30 | have a lien binding, but it's voltage dependent without the change in this |
|
| 38:36 | in the presence of lid that has bounded, it's not going to open |
|
| 38:40 | and conduct anything through it. it's also referred to as coincident |
|
| 38:47 | It's coincidentally detecting the presynaptic neurotransmitter and depolarization of the plasma number. Because |
|
| 38:58 | this, it is thought to have great what we call binding ability between |
|
| 39:04 | happening through synaptic in neurotransmitter release and happening post synaptic depolarization or lack |
|
| 39:13 | So, because of its coincident detection binding properties, it is very important |
|
| 39:19 | synaptic plasticity. Synaptic plasticity occurs either synopsis or weakened synopsis dependent on the |
|
| 39:29 | between the presynaptic and postsynaptic terminals. . And it is very much implicated |
|
| 39:36 | many neurological disorders. Apart from glutamate to an MD A receptor is what |
|
| 39:46 | described as a major inhibitory neurons consider lycee, it serves as a cofactor |
|
| 39:54 | of the scanned white glucose. Uh also acts as a cofactor to B |
|
| 40:00 | an MD A receptor. So the effective way to open it in the |
|
| 40:05 | is not just having the glutamate but also in the presence of this |
|
| 40:10 | factor. And you'll say like where it come from who's releasing gly? |
|
| 40:16 | , you said it's a neurotransmitter. , is there a core release of |
|
| 40:21 | that made of glycine? But you glycine is inhibitory, glycine actually has |
|
| 40:27 | inhibitory function in the spinal cord. why it's considered as the major inhibitor |
|
| 40:32 | transmitter in the CNS. It's the cord interneurons that are within the proper |
|
| 40:39 | cord that will express glycine. We're finding out that the same inhibitory spinal |
|
| 40:46 | will also express glutamate. There's a of those inhibitory interneurons in the spine |
|
| 40:52 | . So despite that fact, you lutein and lying. So if it |
|
| 40:57 | come from vesicles, it's not core , it's sort of a like floating |
|
| 41:02 | or there's a certain amount of pre lying. That's the best explanation I |
|
| 41:07 | . And if it's not there, wash it out from the tissue, |
|
| 41:10 | an MD A receptor in the presence glutamate and depolarization, uh it will |
|
| 41:16 | but not as effectively. So that's glycine is referred to as co |
|
| 41:22 | It's an important cofactor or proper an A receptor function. An MD A |
|
| 41:29 | will have multiple binding sites for even for zinc or illicit drugs like |
|
| 41:36 | P and also for a lot of pharmacological agents as well. Yeah. |
|
| 42:01 | , it still needs, yeah, basically uh it actually needs all three |
|
| 42:06 | them. So it needs to really operate like the presentations that I've seen |
|
| 42:12 | they manipulate the presence of glycine is it doesn't shut down an MD A |
|
| 42:18 | completely if there's no glycine, but doesn't help it, let it operate |
|
| 42:24 | , at its full capacity. So like the best explanation and the presentations |
|
| 42:29 | I've seen so far and that was three years ago or so. |
|
| 42:34 | maybe there's something new that came out the science. Yeah. So, |
|
| 42:40 | you can see ions are passing here and out. Uh and calcium is |
|
| 42:45 | in as well. This is from of your select readings. And why |
|
| 42:55 | I put this here? Because it starts getting into the structure like biochemical |
|
| 43:05 | of this receptor. And it highlights important things. First of all, |
|
| 43:13 | are different glutamate ionotropic receptor subtypes, they have some preserved sequences. And |
|
| 43:21 | , you can read about this full description in your PDF S that are |
|
| 43:29 | in your pages and in your modules maybe even let's see. Yeah, |
|
| 43:36 | is a figure caption because it's uh a a slide that I had |
|
| 43:43 | So when we're looking here, this the linear representation of what we're going |
|
| 43:48 | be looking here in the three And there are different areas in this |
|
| 43:55 | all of these uh two and 3D . So you have the amino terminal |
|
| 44:03 | or A TD here in two This is the structure of an MD |
|
| 44:08 | receptor and this is the a TD here. Then you also have li |
|
| 44:15 | binding domain which is lbd domain right , lbd domain. And uh this |
|
| 44:28 | just from one subunit. So an A receptor would now you cannot see |
|
| 44:35 | probably. So an MD A receptor be die head or America or trhe |
|
| 44:45 | America. What does that mean? , first of all, it shows |
|
| 44:48 | that it contains four subunits, an A those subunits are called glue, |
|
| 44:57 | glue N one, glue N two and asterisk. You can see their |
|
| 45:05 | here, gray and blue. That that those are die heter America that |
|
| 45:11 | sub units have to come together to these protein channels. These are three |
|
| 45:18 | subtypes of subunits. So N a receptor function in the early development |
|
| 45:29 | as the brain matures can be one of these differences is a different |
|
| 45:36 | of the sub units in this It actually has the ability and MD |
|
| 45:41 | receptors to reorganize themselves from, let's N two dominant structures to N one |
|
| 45:51 | two and N two asterisk structures. . And that happens during the early |
|
| 46:01 | . No. What else are we here? We're also seeing the C |
|
| 46:07 | domain which is CTD or we skip . I'm sorry, we are seeing |
|
| 46:11 | transmembrane domain T MD. OK. do you think the T MD? |
|
| 46:18 | is M one M two M three , one M two M three M |
|
| 46:25 | . What are these? These are segments, remember that they have the |
|
| 46:31 | subunit transmembrane segments. So it's embedded there pretty well. C again is |
|
| 46:38 | C terminal or the carboxy terminal domain that MD A receptor subunit called the |
|
| 46:46 | C and LBD. Which is this li and binding domain has two separate |
|
| 46:57 | . S one and S two uh one and S two right here that |
|
| 47:04 | shown on this two dimensional graphic This in B is the chemical structure |
|
| 47:14 | some of the N MD A receptor . And right now, you will |
|
| 47:21 | even understand maybe what they are uh prod which is allosteric inhibitor. Hang |
|
| 47:29 | to the next slide of the two 220. I'm not gonna ask you |
|
| 47:38 | remember names. It's competitive antagonist had in as open channel blocker. |
|
| 47:52 | Why am I naming all of these ? Is all of these different substances |
|
| 47:56 | can modulate an MD A receptor function different size. It's very specific binding |
|
| 48:04 | within this three dimensional structure. So example, this shows that Empro binding |
|
| 48:12 | right here in the A TD This shows the glutamate binding side light |
|
| 48:20 | here in the LBD domain. This the ketamine uh blocker. And also |
|
| 48:27 | another memo blocker that will bind in T MD area of this protein. |
|
| 48:35 | you need to imagine a really complex dimensional structure for each program with many |
|
| 48:41 | and locks, and all these molecules enter into this building through different doors |
|
| 48:48 | D and use different locks and different to open those locks on the |
|
| 48:52 | So this is the, the structure this an MD A receptor with so |
|
| 48:57 | different agents that can bind to This is something that we need to |
|
| 49:04 | . There's a lot of uh diagrams . OK. But we need to |
|
| 49:11 | the fact that different molecules that bind different receptors will exert a different |
|
| 49:19 | Agonists are going to open and encourage MD A receptor function. And typically |
|
| 49:28 | channel or receptor that we talk Agonist antagonist is something that is going |
|
| 49:36 | compromise the function of the receptor or end up closing, it may end |
|
| 49:42 | partially closing it depending on its chemical , depending on the binding side in |
|
| 49:48 | really complex three dimensional structure. What a competitive antagonist on this an MD |
|
| 49:57 | receptor? You have multiple binding sides we're talking about, but we have |
|
| 50:05 | lot of different molecules. So we this, let's say I'm gonna make |
|
| 50:10 | this as a an MD a OK. And it has this binding |
|
| 50:18 | and let's say this binding site. in no particular order or anything, |
|
| 50:23 | say it's a glutamate binding site. what glutamate binds on this receptor channel |
|
| 50:30 | . But so it happens, maybe shouldn't throw a number in here. |
|
| 50:35 | it happens that there is another molecule it, I can't even see |
|
| 50:42 | My son list but there's another molecule is going to compete for that same |
|
| 50:52 | . That means its chemical structure, properties. So lil or whatnot, |
|
| 51:00 | permeability or whatnot and different chemicals. gonna say that this is where I |
|
| 51:05 | to bind to the same spot with binds, that makes it a competitive |
|
| 51:12 | , that makes it a competitive If it's in the in the case |
|
| 51:16 | antagonists, which one wins, not the one that has highest finding |
|
| 51:40 | Mhm Is that this guy maybe it's to have one nana mo or this |
|
| 51:50 | and it's has a very strong attraction you need to have five nano molar |
|
| 51:58 | of of of, of that guy glutamate in order for it to squeeze |
|
| 52:04 | and perfectly position itself into that same . Uh So it's a binding |
|
| 52:10 | Yeah, concentration is important but certain will bind things very, very well |
|
| 52:15 | low concentrations. OK. What about ? What about allosteric modulation? What |
|
| 52:23 | an allosteric modulator? What is allosteric ? I was trying to see if |
|
| 52:33 | a little description here for you with allosteric modulators but there isn't. So |
|
| 52:42 | modulator that means that it binds to different site from one of the known |
|
| 52:48 | bonds. What's that? OK. changed it for formation of, |
|
| 52:55 | So allosteric modulator, allosteric modulator, can be positive if it's a positive |
|
| 53:03 | modulator. That means it's gonna promote flux of ions and the opening of |
|
| 53:08 | channel. If it is a negative modulator, that means it's going to |
|
| 53:15 | to impede with the conductance of that . But notice that there is a |
|
| 53:25 | section here for channel blockers. So versus blocker or an antagonist versus |
|
| 53:41 | So blocker can actually block the It does not necessarily have to have |
|
| 53:48 | binding side, it can squeeze into channel. So that's how blockers are |
|
| 53:53 | blockers will block the channel. You we talked about tetrodotoxin. It's actually |
|
| 54:04 | reversible antagonist. It sticks to the uh te tetrodotoxin. It, |
|
| 54:15 | it, it, it sticks to voltage gated sodium channels for a while |
|
| 54:23 | not forever. So you can reverse binding, but it's an antagonist because |
|
| 54:29 | blocks the channel function that conduct but it is not a blocker. |
|
| 54:35 | to say, so this is just linguistics of uh agonists antagonists, allosteric |
|
| 54:43 | or positive modulators and, and No, thanks. Yeah, it's |
|
| 54:52 | channel blocker. Yeah. Or the a part of the brain physiology. |
|
| 55:02 | has a binding side to it. magnesium has a binding site right |
|
| 55:10 | There's actually I think two findings. and I think there's another one closer |
|
| 55:15 | here. It does not show two for magnesium can get in. Um |
|
| 55:21 | that's based on the confirmation the size also on the interactions with the amino |
|
| 55:28 | residues, the polarity. Oh So not a chemical blocker. It's |
|
| 55:37 | it's an ionic blocker and it's around the brain. So, OK. |
|
| 55:43 | this shows me a little bit And now I'm not gonna ask you |
|
| 55:48 | these names but notice that channel blocker that we talk about. PC |
|
| 55:54 | Kaman MK 808 are channel blockers. P we discussed in the previous, |
|
| 56:04 | an illicit drug. It's a hallucinogen by activating an MD A receptor in |
|
| 56:09 | very strong fashion, can lead to or mental diseases disorders. It could |
|
| 56:15 | chronic, you may be hearing about . It's emerging as a treatment for |
|
| 56:22 | depression. So people call this as anesthesia. So it's, it's |
|
| 56:31 | Ketamine is actually an anesthetic, but proving itself when people get knocked out |
|
| 56:38 | ketamine, they come out happier. So and uh yeah, it's an |
|
| 56:45 | treatment and there are some ketamine depression treatment clinics in Texas and I even |
|
| 56:50 | faculty that are using this uh for , and, and are, and |
|
| 56:56 | saying that it's quite effective actually for uh issues. OK. The last |
|
| 57:02 | that we're gonna discuss about Lunna Masers that we have metabotropic luck. There |
|
| 57:08 | three groups of metabotropic L makers for most part, group one are located |
|
| 57:17 | and group two and group three are now group one that are located by |
|
| 57:24 | , they will interact a lot with with other cellular messengers and cascades. |
|
| 57:31 | they will modulate neuronal excitability. But can also modulate neuronal inhibit or in |
|
| 57:40 | . And the pre cyanic metabotropic glutamate , they're metabotropic because they're g protein |
|
| 57:47 | . So they don't conduct ions through . They don't change, they don't |
|
| 57:51 | to EP SPS. But rather the of these presynaptic metabotropic glutamate receptors and |
|
| 57:59 | and actually block exocytosis presynaptic. it's involved in regulation of synaptic |
|
| 58:07 | presynaptic postsynaptic involved in the excitability of process regulation. And these also can |
|
| 58:17 | more. So, neurotransmitter release and beyond just the exocytosis, these metabotropic |
|
| 58:23 | receptors. This is another representation of this is so blurred, actually looks |
|
| 58:30 | good here. But you have another of different metabotropic ligaments. So you |
|
| 58:39 | them on the pre synoptic terminals, have them on LTO meic pre synoptic |
|
| 58:47 | . That's why I included this picture you also have A G and that's |
|
| 58:51 | I said it also controls the inhibit inhibition ability of those cells too. |
|
| 58:59 | then the postsynaptic ones that communicate with sorts of psychic A MP for |
|
| 59:05 | upregulate down regulate and in addition to location on neurons, they're also located |
|
| 59:14 | glial cells. Ok. So you glean astrocytes that will have these metabotropic |
|
| 59:22 | receptors and there it will control and astro cytic cell activity and there are |
|
| 59:33 | subtypes of these receptors. So there three groups. But within each |
|
| 59:37 | you have several different subtypes of metabotropic receptors. And each one of these |
|
| 59:43 | is gonna be tied to a slightly cellular function or molecule or kinase downstream |
|
| 59:50 | the cells. All right. So concludes glutamate. When we come back |
|
| 59:54 | lecture, we will go through Gaba start going into the dopamine receptor |
|
| 60:00 | And um it's going to be then to the lecrone neuronal imaging. So |
|
| 60:08 | see where we get through the material that one. Thank you very much |
|
| 60:12 | being here and I will see everyone on Thursday. I may take |
|
| 60:19 | uh I mean on uh on this on Tuesday. Yes. Yeah. |
|
| 60:32 | more |
|
