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00:00 Recording. So today is lecture four cellular neuroscience. We're going to continue

00:07 about glutamate. Ergic signaling. We off talking about an M.

00:13 A. Ample and keen eight receptors are pictured here and we said that

00:22 which is a neurotransmitter which our brain make its endogenous. It's an endogenous

00:32 . Endogenous means it's produced inside the agonist. That means it's going to

00:37 these receptors all three of them and three of these receptors also have their

00:44 distinct chemical agonists and those are chemical which are basically exogenous chemicals. Ampara

00:58 chemicals and M. D. And kind eight. And because originally

01:04 same glutamate would activate all three receptors was no way to distinguish them

01:11 It's a very clear way to distinguish because they have their own specific agonists

01:20 empire is not going to bind an . D. A. And an

01:24 . D. A. Is not to buy into an amp and so

01:28 . So we're gonna get in more and agonists and antagonists and a little

01:33 more of this terminology. So the difference between am Paquin aid or what

01:41 call non NMDA receptors is that once is released pre synaptic aly the binding

01:47 glutamate an empire and kinda receptors will for deep polarization and the flocks of

01:54 inside and later for the influx of from inside to outside in the

02:02 And apple receptor is going to be for the initial phase of the

02:10 P. S. B. So we look at glutamate release at this

02:18 here and we are recording from a here And this is the trace from

02:27 neuron here. We're recording activity is to be a deep polarization. So

02:33 talked about resting membrane potential let's say syllables and this can go to let's

02:39 -15 syllables. There's going to be deep polarization which is excitatory, post

02:48 potential. Excitatory p poss synaptic posson optic potential. And the early

02:59 phase of this E. P. . P. Is because of the

03:03 A receptor. And the reason why because as soon as glutamate is released

03:10 binds to a receptor that is going be influence of sodium. This later

03:17 of E. P. S. . Is mediated by N.

03:21 D. A receptors. And the for it is first of all,

03:32 M. D. A receptors have binding site for glutamate. It has

03:38 binding site for glycerine as a co and inside of the channel and has

03:45 binding side from magnesium and magnesium is this channel. And in order for

03:55 block to be relieved there has to a deep polarization that happens initially through

04:04 amper receptors. So emperor receptors first the initial D polarization and that allows

04:11 the magnesium to get kicked out of M. D. A receptor opens

04:16 M. D. A receptor and . D. A receptor is responsible

04:19 the late portion of the E. . S. P. So a

04:25 of things here that receptors they will about 20 PICO cements of current and

04:36 M. D. A Will conduct Pecos emails of current. So the

04:44 it's a larger poor and more islands flux through that poor in the end

04:50 M. D. A receptor essentially more to the post synaptic deep

04:56 But it takes time to wake it because each one of these receptors we

05:06 about has their own agonists ampara and . D. A. Kind

05:11 They also have their own distinct So ALpa is going to get blocked

05:19 kind Nate are both going to get by a substance called C.

05:24 Q. X. And an D. A receptor is going to

05:30 blocked by a substance called A V. Or 85. So blockers

05:39 antagonists sometimes can be used interchangeably antagonists will also either diminish or block or

05:50 of certain receptor channels. Because an . D. A receptor has to

05:58 the pre synaptic neurotransmitter release and binding glutamate and because it has to sense

06:05 post synaptic deep polarization for this magnesium leave the channel, it is referred

06:11 as coincidence detector. We say that has slow kinetics because it's responsible for

06:21 late portion of the PSP. So fast kinetics and the initial activation and

06:27 D. Polarization is through the ampara an M. D. A receptor

06:33 sample keen and the late portion as an N. D. A.

06:39 some uh glutamate receptors. Meadow below , ample canaanite and N.

06:50 D. A receptors are ion a . Their eye on a tropic because

06:57 binding chemical glutamate binding to this receptor open the actual channel poor and allow

07:06 the flux of ions. That's why ion a tropic and then all of

07:12 M. D. A receptors, going to be the flocks of sodium

07:19 and calcium for ample only some of ample receptors will allow for the flocks

07:26 cows. So the eye on a nature of these channels and what ions

07:33 through these channels is also different and entering inside the south is not contributing

07:41 much to the charge as much as may contribute to synaptic transmission and it

07:49 contribute to the cellular processes calcium two ion can act as a secondary messenger

07:58 the cells to. Now this receptors here are metabolic tropic glutamate receptors and

08:08 this case glutamate will have a binding of these on these receptors. But

08:14 of opening a channel or on this to which it binds it is now

08:22 to cause a downstream cellular reaction by g protein complexes and this g protein

08:33 once they get activated and these subunits catalyzed they can cause activation of other

08:41 messengers enzymes in many different functions inside cell including altering the transcription factors.

08:54 is what we call the basic mode operation of G proteins. So if

09:03 can see that G protein coupled receptor you have this jew protein which is

09:10 either associated or bound to the G coupled receptor and you have a transmitter

09:18 binds to this receptor and B. doesn't open the channel for poor but

09:25 it activates the alpha subunit of this protium and this alpha subunit and beta

09:38 subunits. They disassociate one from Alpha. Now can target This effect

09:47 protein one and can stimulate this effective and beta gamma subunit, the other

09:58 of it can also influence the effect proteins nearby by binding to them.

10:07 a lot of these proteins, maybe associated proteins. This is the basic

10:14 of operation. Is that ligand never and to the cell of course ions

10:21 flux through the receptor. But alpha this catalytic activation of these subunits is

10:35 in changing ion flux is through nearby or changing intracellular signaling in general.

10:47 , so in your class documents and blackboard you have lecture reading and supporting

11:00 . For example, when we talked the hippocampal circuit, there is information

11:08 that article and the figure that we when I uh we were discussing fragile

11:16 syndrome and spines and I pointed to article, this is the link to

11:25 article, fragile X. The following that you're seeing here. Not this

11:31 but this one it's actually from this which is glutamate ergic mechanisms related to

11:47 . We'll review this in a second . I've uploaded a description of uh

11:59 basically an M. D. Receptor physiology from Quillen College of Medicine

12:09 in Cleveland clinic. So what are of the things that are important that

12:16 noted here about an M. A receptor the prime or excited to

12:22 in the human brain glutamine. It integral role in synoptic elasticity. Why

12:35 M. D. A receptor is positioned to bind the activity from pre

12:41 and Tosin optic sells because it has recognize pre synaptic cellular neurotransmitter. It

12:48 to have passed synaptic deep polarization. it has to have basically there's two

12:57 and and because of that it's at at the crew of the synaptic

13:08 Now it says its synaptic plasticity is to be the basis of memoir information

13:13 FDA receptors are very important here. if plasticity is a cellular mechanism to

13:24 and memory that means N. D. A function which is crucial

13:28 plasticity is crucial to learning and The other thing that's noted here and

13:36 . D. A. Receptors appear have involvement in a process called excite

13:40 toxicity excited toxicity may play a role the path of physiology of variety of

13:48 such as epilepsy or Alzheimer's disease. what is excited toxicity If an

13:56 D. A receptor function is the flux of calcium inside the cells

14:04 cause what is called calcium exciter And too much calcium inside the south

14:11 actually turn on mechanisms that can eventually lead to apoptosis and neuro degeneration if

14:18 is uncontrolled calcium levels. So now have excited toxicity. This excited toxic

14:25 and an M. D. A function here is very important tight control

14:30 opening and closing of an M. . A receptor. The flux of

14:33 inside the cell. Many drugs inhibit M. D. A receptor including

14:40 and Tensai claudine to common drugs of but also ketamine is there is not

14:52 drugs of abuse. They also are drugs as well. Yes so let

15:01 like in India receptors like the excitable would be like tetanus type stuff.

15:09 Except that in the brain you would that a seizure. Yes precisely.

15:15 much of glutamate. Too much of tampon and controlled an M.

15:20 A. Activity can lead to abnormal and yeah a similar similar physiology will

15:28 into that a little bit later in course similar physiology etc. And muscular

15:33 but in the brain it would be synchrony in seizures. So yeah well

15:41 this is introduction cellular of course we discussed that glutamate Nate. They're all

15:53 a tropic? It has subunits and or two and 3. Okay and

16:06 has extra cellular ligand binding domain and trans membrane ion channel when ligand binds

16:13 M. D. A receptor ligand domain closes like a clam shell.

16:20 closure leads the opening of the trans . Our ion channel come back to

16:24 in a second and M. A receptor. You can read this

16:32 . All of these things that we here are kind of a reviewed in

16:36 detail and this is a really good read of about three pages and we're

16:43 going to go through everything here. we already did. We talked about

16:49 detector for example calcium serves a secondary . It's important for development of the

17:03 myriad of functions with central nervous So it has a lot of functions

17:09 is involved in a variety of disease including Alzheimer's huntington's epilepsy stroke, major

17:15 , tinnitus, which is ringing in air's anti NMDA receptor, encephalitis,

17:21 metal poisoning, migraines. Mhm aside significance and M. D. Receptors

17:29 pharmacological target of both therapeutic drugs and abuse. So ketamine, an MD

17:38 sedative and aesthetic off label as an or recreational is hallucinogenic drug of abuse

17:45 there's actually anti depression treatments with with ketamine to ethanol. Common recreational target

17:56 is um M. D receptors through mechanisms. It's just find this common

18:02 drug it's served on campus. So a lot of a lot of

18:11 Okay so you'll say my my my do I need to know all of

18:15 stuff the details the disorders and stuff that. No. All of the

18:21 that we've so far discussed in this this page here. Introduction and cellular

18:27 are the things that I'd like for to be responsible for in the first

18:31 and as far as the knowing what it's involved in, we actually going

18:36 go into that a little bit But the fact that it does seem

18:41 be important for learning and memory, does seem to be really important for

18:44 side a toxicity from which you can seizures in epilepsy and a slew of

18:48 neurological disorders then that that is important know for for our purposes.

18:58 the other thing that I had on in this slide actually is that there

19:05 PCP hallucinations, schizophrenia. MK What that illustrates is that each one

19:13 these receptors will have multiple binding sites different substances. Some of our natural

19:21 endogenous others are natural exogenous agonists and , others are chemicals that are

19:30 illicit drugs and things like that. what is important is for us to

19:37 looking a little bit broader to glutamate and how does the world interpret glutamate

19:45 ? This is a good review that like to use. And let's start

19:52 that. So, first of all said there is ample receptors and then

19:57 who who keeps track of all of subunits. So there's actually these bodies

20:03 union basically clinical pharmacology and then they another regulatory and standardization bodies actually have

20:13 keep track of these things. And today we're gonna be looking at glue

20:17 two receptor structure which is ample receptor . But all of this norman

20:26 if you look at these blue to cake, blue cake, green,

20:31 , green blue and there's a slight between naming and two non monocultures Hugo's

20:41 gene based but in short you still ample N N. M.

20:48 A receptor families. There's a glutamate receptor that we don't mention and talk

20:54 about this course. Alright, so look at this what is illustrated here

21:00 is in our notes. So first all the structure we have sub units

21:05 each one of these subunits in this we're looking at the glue A two

21:11 is ample receptor is comprised of these membrane M 34 and this inter membrane

21:21 em to having them basically four trance slash numbering and started components. There

21:34 the H two and terminus nitrogenous terminus is on the outside it's extra

21:45 Then there is C. 00. terminus which is intracellular the S.

21:57 . Agonist binding residues. So you S one In Orange & S.

22:06 in Turquoise. Is this nice purple here called flip flop. So it's

22:19 it's a region that has either flip the flopped structural configuration in the ample

22:26 and that distinguishes similar ample receptors structural functional. So in the previous paper

22:37 said that when the agonist binds to receptor the clamshell closes and this illustrates

22:47 B now kind molecule which is binding . It will also activate ample receptors

22:56 binding here between the S. One S. Two regions. So now

23:02 looking from the top here. One. There's two regions here,

23:07 flip flop flop region here. And then it says here this is

23:16 kindness stagnant molecules black with a deep of the protein the two disqualified bonded

23:23 and yellow. This is what we the bag bone, the representation of

23:30 going on and where this kind of is found and so when kinda binds

23:37 the side between S. One and . Two, this clam shell kind

23:45 a comes from closes together. So lot of the agonists may be partial

23:55 , you will hear that antagonists are or the full agonists. What makes

24:02 full agonist is more of that clam closer you would see there the more

24:10 the structural conformational change the receptor undergoes is likely going to open it more

24:17 or have it open for a longer . As an agonist partial means that

24:25 may bind to a side but it cause a partial closure of this clamshell

24:33 may not be as effective at opening receptor channel for here in the sample

24:44 . This is a a figure that actually in your lecture notes also.

24:52 this is the next figure that discusses antagonist modulators. So let's talk about

25:02 again by looking at the actual Well, screaming. Okay, so

25:23 because I think it's better resolution. you have this amp kinase receptors and

25:30 have first of all major domains binding for agonists, antagonists and modulators in

25:38 ligand binding domain which is L. . D. This orange domain,

25:45 . B. D. Amino terminal . Right. We just looked at

25:51 amino terminus, the Mh two domain is A. T. D.

25:55 the extra cellular side of the of receptor protein and the trans membrane dough

26:04 , T. M. D. green. The receptor targets of Ligon

26:12 for one or several subunits are listed parenthesis and kind and indicates that the

26:18 selectively selectively targets glue A or glue receptor subunits respectively. Okay, let's

26:24 at this. So look at There's different substances basically will bind to

26:34 portions. So a single receptor is a door that has like 20 potential

26:43 and each one of these locks will for that door to either open partially

26:51 a lot open halfway, stay open a long time once its open or

26:56 in the case of antagonists keep it . Does't matter what happens. So

27:03 the point. I'm not going to you to tell the difference where there

27:10 uh an era system of cyclo thighs versus and uh zinc or magnesium binding

27:22 . But the point is to illustrate multiple binding sides. And the second

27:29 here is to talk about agonists agonists the molecules that are going to open

27:38 this case the receptor channel. But if they're acting through metabolic tropic receptors

27:46 going to basically cause the Cathal Asus that G protein once it binds to

27:51 receptor target. So that's an agonist antagonist is something that is going to

28:00 or cause a closure the third The same as you. You can

28:06 a partial versus full agonists. You also have partial versus full antagonists.

28:22 . Now there is another term that didn't try down here but I would

28:27 for you to know it's called competitive and competitive antagonist is an antagonist but

28:42 competing with the agonist for the same site. So a lot of times

28:51 and antagonists they will have their own binding sites on this three dimensional structure

29:00 target a different sequence of amino But if it's a competitive antagonist that

29:06 it's going to compete for the site agonists are supposed to activate the receptor

29:17 and it's not going to allow for receptor channel to be activated. So

29:23 a competitive antagonist is competing with the and it's not allowing for the agonist

29:30 buy into that receptor basically like and . Mm enzyme inhibitors versus maybe they

29:50 probably yeah absolutely would have similar substances compete for for inhibiting their function versus

29:59 their function and there's probably similar So in this case because we're talking

30:07 endogenous exogenous pharmacological drugs that will be all of these different sides and

30:15 D. A. Receptor involved in and memory involved in all of these

30:19 disorders having a variety of all of binding sites as it's discussed in one

30:25 your taxes a huge target for drug . So because there's so many different

30:35 in so many different ways you can and the significance of the actual target

30:40 this case an M. D. receptor is pharmacological target. Okay so

30:51 there are also Alice Terek modulators. so when we talk about modulators we

30:59 about Alice Terek modulated which means that will have and they can be Alice

31:06 agonists and they can be al hysteric Which bio hysteric means that they will

31:16 a different binding site. There's still 02 molecules can activate that receptor uh

31:28 the same with an antagonist. So molecules can block or inhibit the function

31:34 that receptor but they will do it binding in two different sites. They're

31:39 competing for the same sides. They're a replica of each other. They

31:43 have two different ways of approaching that . So a lot of times actually

31:53 uh talk about Alice Terek modulators if and antagonist and sometimes maybe a better

32:02 is a negative Alistair IQ modulator versus positive Alistair IQ modulator. Because you

32:10 think of negative Alistair IQ modulators, that will impact the function of whatever

32:16 being activated, antagonized uh in an function. And a positive Alistair IQ

32:25 would be like a booster but it be a booster to both agonist to

32:30 on function or two antagonists to boost function. So the better way of

32:35 about uh hysteric modulators. His negative hysteric versus positive al hysterics because they

32:42 affect the functions of both the agonists antagonists. Okay, so we're going

33:00 skip a lot of information on this and then again in this particular tax

33:06 would just invite you to look through figures, the figure legends and maybe

33:13 associated text in those pages to those . And of course, by all

33:19 , if you're interested in in general the whole article, it's it's it's

33:26 that long. It's only both pages so. And it's a overview introductory

33:33 . It comes from the jaspers mechanisms epilepsy sees a lot of what we

33:42 about excitation and inhibition a lot of functional information about what cells do came

33:51 from research and epilepsy and seizures because is such a cell activity disorder that

34:00 can record and analyze that allowed us understand the how different cells function,

34:07 they communicate with each other, how are involved. And so when we

34:14 about Glee um we talk about tripartite , we're gonna come back a little

34:19 and talk about glee in here Now is in particular potential mechanisms by which

34:26 could boost astra acidic glutamate release. this is a scheme here and while

34:36 talking about it here because glutamate Clarence part and synthesis the amount of glutamate

34:42 is available to neurons is regulated by and ostracized in particular. So we

34:50 control of a specific limit released by protein coupled receptors. It's glutamate which

34:59 acting on measurable tropics. So this em just like we learned about

35:06 A subsequent K. V. The stands for voltage here I am and

35:15 small case and blue are five and . Stands for metal but tropic glutamate

35:20 five. So that's what G protein receptor And it's activated by glued in

35:28 . Now we'll talk about what it and a T. P. Is

35:33 molecule but it's also a T. . Is a denizen triphosphate 80

35:40 Is also a neurotransmitter in the brain there are metabolic tropic receptors on glia

35:48 are called P. Two Y one . So the metabolic tropic receptors they're

35:56 linked to this G protein called G G Queer and what G.

36:07 Does and astra sides is it regulates amount of calcium. It has to

36:17 a certain amount of calcium and communicates calcium waves. So Glia does not

36:23 with each other through action potentials, through calcium waves, sending these waves

36:30 electrical gap junctions through the synopsis that electrical synopsis. They're all interconnected through

36:37 electrical networks and regulating the control of specific glutamate release. So on the

36:46 have a normal situation and a lot neurological disorders. And we'll be discussing

36:54 in the scores a lot of times significant inflammation in the brain. In

37:01 it will hear sometimes talks on Alzheimer's that says the brain on flames and

37:08 talks about inflammation and one of the of inflammation is that it is in

37:17 brain controlled like leo's house and it controlled this inflammatory immune response in particular

37:27 controlled by micro glial cells. But the ostracized sides can play a role

37:36 this process. And if there is levels of inflammation and inflammation in the

37:43 can happen following a brain injury. can happen following an infection in the

37:49 viral infection. Meningitis, bacterial or infection. It can be because of

37:59 like I said trauma but it can potentially even a genetic or environmental causes

38:07 toxicology chemicals that can cause inflammation of brain and it can lead to glia

38:17 reactive and this process is called reactive sis and during the reactive reality sis

38:26 is shown here on the right is in the epileptic grade. This is

38:33 example where in epilepsy because of the activity in neurons you will also have

38:42 aosis. And during the reactive Rios what you have is M Glue.

38:48 . Five. This ion metabolic tropic receptor and it says activated microglia.

39:01 micro glia are essentially over activated and are five, gets up regulated now

39:07 glued innate that gets released and bind glorify on glial selves. So wait

39:18 second. He first told us about . Now you're telling us about metabolic

39:25 glutamate receptors. So don't confuse these with the tripartite synapse schematic. That

39:34 about the cycling of glutamate. It's important glutamate in the end and how

39:40 of glutamate is produced. But it is released by excitatory neurons will

39:47 to Mettomo tropic receptors. Anglia. so Gloria doesn't have uh the the

39:57 . Kind eight and then D. . They have metabolic tropic and glue

40:02 five and in the case of reactive and inflammation you have over expression of

40:09 . That means there's too much of receptor over expression a lot of times

40:14 that this glia is going to start more of this protium and inserting it

40:22 the number and when it does So the same glutamate levels can trigger abnormal

40:31 in glutamate abnormal increases of calcium and regulation of of glutamate release from

40:43 So glia control glutamate level. You to have normal function of in blue

40:48 five through this G. Q. control normal levels of calcium, a

40:53 cycling of glutamate. But if you regulate this is one of the mechanisms

40:59 reactively aosis and you increase calcium cycling you increase the glutamate release and availability

41:08 neurons. You're just perpetuating the imbalance excitation and inhibition. But now you're

41:14 that imbalance through reactively aosis and through cells. So as well as reactive

41:26 release TNF alpha which acts on N. F. R. One

41:31 in the pathway that promotes prostaglandin. formation. Prostaglandin in turn activates a

41:39 . Q couple prostituted receptor that boost astra site calcium release and thus astra

41:46 glutamate release. So there's another loop and some of their nose. But

41:53 are some of the cellular mechanisms by you have abnormal flux of glutamate and

42:01 of glutamate exacerbating some of these disorders epilepsy but in this case from from

42:09 perspective not from too much neuronal activity too little inhibition but from glutamate and

42:15 from transporter but through actual intracellular cascades calcium regulation through the glue dramaturgy through

42:26 glial uh cellular cascades. So it's interesting and challenges and opportunities uh major

42:39 for using information. New anticonvulsants because is for epilepsy. But I think

42:45 major challenges still remain for really effective that use these an M.

42:50 A. And AMP kinase receptors finding of G alpha Q coupled receptors such

42:58 masculine IQ. And potentially the activation America kinda receptors. So there's all

43:03 of complex interactions going on in the with other chemical systems as well.

43:10 so this is uh pretty pretty It's just a little bit more about

43:19 physiology that we're gonna go into understanding E. P. S.

43:24 S. And the conductance is. then we're gonna kind of start going

43:30 the excitation and the recording of the single channel currents more of the G

43:38 and then we're gonna go into inhibition to gather. So for Gaba I

43:45 have a an equivalent sort of a pager. Well it's a little bit

43:52 than one page. But again, we're gonna touch upon what you will

43:55 responsible for the exam is pretty much for Gaba is um summarizing in the

44:03 couple of paragraphs. But Gaba is major inhibitor neurotransmitter and we're going to

44:09 back to this in the second or about an hour or so. So

44:19 think that this diagram here just illustrates confirms what we already discussed pharmacology.

44:30 have their own agonists antagonists, genetics fast early phase of E.

44:39 S. P. This is really screen. I really I need to

44:44 it. We'll report you screen. kinetics passports are slow selectivity selectivity for

44:53 ions they conduct. So calcium always calcium sometimes throughout conductance. An

45:04 D. A. Large conductance. pick a seaman's ample receptors not so

45:11 , and M. D. A is blocked up with magnesium block

45:14 So it's a coincidence detector. And we started discussing some of the recording

45:23 . So I think because there's just a few of you in class

45:28 maybe this could be a good stopping on uh odometer GIC physiology. Because

45:36 we go and into more glue dermatologic recording methods. We will talk about

45:46 cellular versus wholesale recording methods and some the experimental techniques that we use in

45:54 lab. And then as far as will probably spend uh maybe 45 minutes

46:03 so to an hour in Gaba. we'll continue, we'll call it uh

46:10 in eight Uh dermatologic three and then go into urgent. Okay so this

46:18 conclude today's

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