"Drugs and the Brain" - New course from Coursera

[at0m]

https://www.coursera...e/drugsandbrain

Next Session: Dec 1st 2012 (5 weeks long)

Workload: 4-6 hours/week

About the course

What happens in the body when a person smokes a cigarette? After several weeks of smoking? When a person takes antidepressant or antipsychotic medication? A drug for pain or migraine? A recreational drug? Neuroscientists are beginning to understand these processes. You’ll learn how drugs enter the brain, how they act on receptors and ion channels, and how “molecular relay races” lead to changes in nerve cells and neural circuits that far outlast the drugs themselves. “Drugs and the Brain” also describes how scientists are gathering the knowledge required for the next steps in preventing or alleviating Parkinson’s, Alzheimer’s, schizophrenia, and drug abuse.

About the instructor(s)

Henry A. Lester, Ph. D., is Bren Professor and Executive Officer for Neuroscience at the California Institute of Technology, where he has spent his entire teaching career. He has written almost 300 scientific papers and holds seven patents on drugs and the brain, including topics such as nicotine addiction and Parkinson’s disease. He served as President of the Biophysical Society and as a member of the Advisory Council of the U. S. National Institute of Mental Health (NIMH). He has conducted research sponsored by the California Tobacco-Related Disease Research Program, the Michael J. Fox Foundation, the McKnight Endowment for Neuroscience, NIMH, and the National Institutes of Drug Abuse, Neurological Diseases and Stroke (NINDS), Aging, Heart and Lung, and General Medical Science. He received the Fuller Award in Neuropharmacology from the American Society for Pharmacology and Experimental Therapeutics, the Cole Award in Membranes from the Biophysical Society, and two NINDS Jacob K. Javits Awards. He received degrees from Harvard and Rockefeller Universities.

[Fluss]

Already signed up! :D

It feels good to have a scientific bit of knowledge about it.

[poisonshroom]

Looks good - I was going to sign up for it too

Some of the other Biology ones look interesting as well

Edited November 28, 2012 by poisonshroom

[Darklight]

OMG. Halfway through the introductory lesson and my whole brain exploded. At about 3.30min

Excellent looking course, but it may well be over my head

Why the fuck can't I understand this stuff?

[Darklight]

Hmm, on reflection, maybe they could break this stuff down better. It's a long jump between the " ooh look we have lots of synapses" pic and the incredibly complex pic in the next slide- and after that " Here’s the acetylcholine binding protein interfacial “aromatic box” occupied by nicotine"

After that the video just seems to go on and on half explaining things, such as- is the nicotine receptor capable of binding only one molecule of nicotine? The pic is misleading- the lines which could approximate the zoom area could also represent additional binding sites for other nicotine moleules

And yes, I do need to look that up, but it looks to me like simpler explanations are possible here and having to try to work out what is going on is detracting from my learning experience.

The trouble with being an expert is that it is easy to forget what it's like to be a beginner

[Alchemica]

Thankfully there's a vast collection of websites to copy and paste, or seek your own answers from The receptors in question are unkindly complex (...and still have mystical unravellings to go in science) - I really don't think the course is starting from a good grounded base for anyone.

Community 'group-effort' thread time?

You came to the same conclusions (as follows), Darklight?

-neuronal nACh receptors can be structurally different from peripheral nACh receptors

'The binding of acetylcholine to nicotinic AChRs brings about their activation. When two molecules of acetylcholine [or agonist] bind to a nicotinic AchR, a conformational change occurs in the receptor, resulting in the formation of an ion pore. Nicotinic receptors are always pentamers, with the subunits arranged symmetrically around a central receptor channel. The receptors always contain two or more alpha subunits, which are critical in acetylcholine binding. The acetylcholine-binding site is comprised of a dimer formed by the alpha subunits (principal component) plus an adjacent subunit (complementary component), where binding to both sites is required for the channel to open.' [link]

The pore can switch between an open and a closed state on binding of two molecules of acetylcholine to the two α subunits at sites within the channel. Although the channel alternates between an open and a closed state, binding of acetylcholine increases the probability of the channel being in its open state. Nicotinic receptors are of the ionotropic type which, on stimulation by

acetylcholine, nicotine or related agonists, open to allow the passage of sodium ions into the neuron. There are structural differences between the peripheral and neuronal receptors, the former being pentamers composed of two alpha and one beta, gamma and delta sub-units while the latter consist of single alpha and beta sub-units. It is now known that there are at least four variants of the alpha and two of the beta sub-units in the brain.

Source

more.

[Darklight]

Community 'group-effort' thread time?

You came to the same conclusions (as follows), Darklight?

 

Heehee no, sorry, you give me waaaay too much credit for smarts.

My first thought was " how the hell did they jump to that degree of difficulty in the intro lecture?"

My second was- " no way did they explain this properly, the diagram doesn't make sense as a standalone". Diagrams should support examples, not detract from them, and most of the ones I've seen there so far are confusing

I hit them up about it on the discussion forums and was told that it was only the first intro lecture and an indication of what we would be learning on the course, rather than something we were expected to grasp immediately and early on. Phew- but it would have been nice to see this explicitly emphasised in the lecture

I don't think I'm exactly dumb, but I'm often understanding-challenged ;) Add to that my problem with processing further information until I understand exactly what's in front of me- maybe I'm too literal to just take stuff on board and worry about it later- and I find learning in a formal and hands-off environment extremely frustrating.

Hands on stuff, no worries.

I've found it really frustrating in the past when dealing with some academic or research staff who are out of touch with recent best practice at the bench though, I remember a spate of it about ten years ago. Good theory is very necessary in experiment design but if a researcher hasn't sufficient bench experience the experiment can be irrelevant if they fail to take into account the extra variables that a physical experiment in real time adds. I'm wondering if I'm better at the bench because the learning curve is slower and the number of experiments one can physically wrangle in a set time frame does limit the amount of new information I need to process? Or is it just that academic learning hasn't worked for me because I'm asking too many questions in my head about how it all fits together so I can actually do something with it? I wish I could overcome this, it's hell frustrating

I wonder if learning science is like learning music? I've taught a few people music, and for the theory work in the early stages it's just a case of plug along and eventually the light goes on. It's a closed system that doesn't make sense until it does, if you get me

Thanks for all your help mate, I'm going to try to stick with this, it looks to be about 20hr a week, but hell, I bought the textbook and I refuse to let it be just another one in the pile that I'll read some day

Edited December 7, 2012 by Darklight

[Darklight]

When two molecules of acetylcholine [or agonist] bind to a nicotinic AchR, a conformational change occurs in the receptor, resulting in the formation of an ion pore. .... binding to both sites is required for the channel to open.'

 

OK, thanks for that. All I could understand from your kindness tho is that more than one molecule of acetylcholine can bind to the nicotinic receptor. From the diagram I saw in the intro lecture it looked as though only one molecule could bind and it looked wrong, it was just a tiny point on what looked like a much larger receptor.

What's the theoretical minimum/ maximum humber of molecules which could bind to that receptor. One? Two? Do these number of minimum/ maximum binding hold for all receptors/ molecules? Can other things bond to the receptor as well even though one or two molecules of acetylcholine are already bound? If so, how does this affect receptor behaviour and any downstream processes?

The term 'bound' seems to be misleading and ambiguous, at least to my understanding. There is a difference between a molecule that is plugged into a receptor and one that is bouncing in and out. If I'm wrong here can someone clarify?

The pore can switch between an open and a closed state on binding of two molecules of acetylcholine to the two α subunits at sites within the channel. Although the channel alternates between an open and a closed state, binding of acetylcholine increases the probability of the channel being in its open state.

OK I saw the alpha subunits (thanks! ) and I now understand that there are two structural types of receptors in the peripheral and neuronal receptors ( that should have been made clear in the diagram, but you fixed it for me ) Does the channel pulse between open and closed as a part of normal function, like a sea anenome? ( excuse the clumsy metaphor )- or is that only in the presence of an activating molecule of a particular type, the acetylcholine specifically causing the channel to remain open longer when it is bound, and other molecules like nicotine will cause different behaviour in the receptor

There are structural differences between the peripheral and neuronal receptors, the former being pentamers composed of two alpha and one beta, gamma and delta sub-units while the latter consist of single alpha and beta sub-units. It is now known that there are at least four variants of the alpha and two of the beta sub-units in the brain.

Ooh that makes sense, are they all lumped together under the same receptor because they all respond to the same chemical stimulii? Or is the nomenclature kinda like chem, with lots of archac stuff left in and you just have to know. Or do they slug this out like taxonomists behind the bike shed?

you rock, btw

[Alchemica]

"The channel usually opens rapidly and tends to remain open until the agonist diffuses away, which usually takes about 1 millisecond. However, AChRs can sometimes open with only one agonist bound and, in rare cases, with no agonist bound, and they can close spontaneously even when ACh is bound. Therefore, ACh binding creates only a probability of pore opening, which increases as more ACh binds" [nAChR wiki]

Summarising a review:

The receptor binding sites can be empty, or one or two binding sites can be occupied (singly, or doubly-ligated respectively - Ligand wiki, Protein-ligand wiki, Receptor Binding wiki); in each state of receptor occupancy the protein can undergo the transition between the closed and open states.

- the binding sites on the acetylcholine receptor are not equivalent

- singly-ligated receptors produce brief-duration channel openings.

- doubly-ligated receptors produce channel openings with longer durations.

- driving force for channel opening is the increased affinity for the ligand of the open conformation

- 'allosteric theory' [history] helps to explain the phenomenon of cooperativity exhibited by multisubunit, multi-binding site proteins.

- the allosteric transition has a clear experimental manifestation of sigmoidal binding and dose-response behavior.

- the binding and dose-response experiments on allosteric proteins give the appearance of a single site with an effective affinity that is the product of a true affinity and a conformational equilibrium constant.

- during normal receptor function the unligated and singly-ligated open states play no significant role so they can be neglected in a simulation of synaptic function.

- the rates of the binding transitions are proportional to the concentration of acetylcholine.

"Channel opening is concomitant with a change in the binding site to increase affinity. Occupancy of just one site will increase the probability of the entire protein assuming the open conformation, and since the open conformation binds ligand with a higher affinity the net effect of occupying one site is an apparent increase in the affinity of the other sites. In this way, the cooperativity of the allosteric transition confers cooperativity on ligand binding.

Each subunit is allowed to bind equivalently, but when it comes to the conformational change an important restriction is introduced by insisting that all of the subunits undergo the transition in unison. Thus, the allosteric transition is intrinsically cooperative; separate transitions by individual subunits are not allowed. This is a far-reaching assumption that provides a potent, albeit indirect, mechanism for the binding sites to interact with one another."

- packing of subunits at their interfaces is assumed to force all of the subunits to undergo the allosteric transition in a concerted all-or-none fashion.

- occupying one of the sites in the tense state lowers the free energy barrier for the cooperative conversion of entire protein to the relaxed state. By making it easier to form the relaxed state with its higher affinity, the affinities of the other empty binding sites are effectively increased.

Experimental relevance: An experiment in which binding site occupancy is measured as a function of ligand concentration will give the appearance of being governed by only one binding site; the open state should bind acetylcholine more tightly, but because of the rapid interconversion with the closed state, these two conformations behave like a receptor with one apparent affinity. The low-affinity receptor detected in experiments thus represents mixture of closed and open channels.

- the true binding affinity of the closed state for agonist can be measured because the rate of opening is proportional to the fraction of receptors in a ligated closed state.

- the second binding site has a much lower affinity than the first binding site and on and off rates obtained in this way show the dependence on acetylcholine concentration expected for a binding process. From these data the affinities of the two binding sites were shown to differ by a factor of about 100

- binding sites have intrinsic differences prior to binding

- they are not capable of influencing one another except through an allosteric transition.

"Channels can be seen to flicker rapidly between the open and closed states during bursts of activity. The closures during a burst represent ligated receptors with closed channels. This observation thus demonstrated discrete transitions between two states for a fixed state of receptor occupancy. On the other hand, in the absence of ligand, channels can open spontaneously, showing that the two conformations are still in equilibrium even when the binding sites are empty. In the ligated receptor the channel opens about 10⁵ times more rapidly than in the unligated receptor.

As the concentration of an agonist increases, the relative frequency of these long-duration openings increases. The true binding affinity of the closed state for agonist can be measured from these kinds of experiments because the rate of opening is proportional to the fraction of receptors in a ligated closed state. The true binding affinity of the closed state for agonist can be measured from these kinds of experiments because the rate of opening is proportional to the fraction of receptors in a ligated closed state.

Molecular analysis of receptor structure turned out to be a more effective way of determining the basis for different binding affinities. An intrinsic difference between the two sites is in excellent accord with what is known about the structure of the acetylcholine receptor. Although the binding sites are primarily on the two a subunits of the receptor, the pentameric arrangement of the subunits forces the a subunit into nonequivalent environments. The delta subunit is adjacent to one of the a subunits, and the gamma subunit is adjacent to the other a subunit. Each of these adjacent subunits contributes structurally to its respective binding site."

Physiological:

"Spontaneous channel openings when acetylcholine is not being released from the nerve terminal would clearly be harmful if enough current were generated to collapse the membrane potential of the postsynaptic cell. However, in an unligated receptor the equilibrium constant for the allosteric transition is so low that the current from spontaneous openings is somewhat smaller than the ambient leak current of a muscle cell membrane . Thus, spontaneous openings do no harm. By contrast, when acetylcholine is bound, the equilibrium constant for the allosteric transition of doubly-ligated receptors is high enough for the channel to be open more than 90% of the time to generate a near maximal postsynaptic current from each receptor that binds acetylcholine."

The presence of two binding sites can be seen as an adaptation of the protein to:

- gain the additional binding energy needed to gate the channel

- allow activation and termination of a synaptic response to be fast and sensitive

With a sufficient number of channels opening at once, the inward flow of positive charges carried by Na⁺ [etc.] ions depolarizes the postsynaptic membrane sufficiently to initiate an action potential.

"A singly-ligated receptor has an equilibrium constant for the allosteric transition of well below one, dissociation of only one of the two bound molecules of acetylcholine will reduce the response considerably. In this way making the dissociation rate constant of one of the two binding sites very rapid and providing for rapid deactivation upon acetylcholine removal, without sacrificing high sensitivity and rapid activation by acetylcholine."

On receptor types

Membrane potential

Full example of topic with nAChR

Edited December 10, 2012 by Alchemica
more links

[Darklight]

"The channel usually opens rapidly and tends to remain open until the agonist diffuses away, which usually takes about 1 millisecond. However, AChRs can sometimes open with only one agonist bound and, in rare cases, with no agonist bound, and they can close spontaneously even when ACh is bound. Therefore, ACh binding creates only a probability of pore opening, which increases as more ACh binds"

OMG Alchemica, thanks so much- I've spent the last two days looking at your response and trying to integrate what I can

Above all it's this which has made me decide to drop out of the course. If this is the level of confusion I get from the first 10% of the first week- and it was a slide from practically the beginning- I really can't see how I can finish the course

I think I'll just download all the week 2 lectures notes and videos and then sign out. It's a shame, but this is not a 4-6hr a week workload ( as advertised ) for me and is not the right time for me to dedicate the 20-30hrs I'd need to even come close to getting a grip

Damn shame they don't run these like apprenticeships, I'd happily become an apprentice and do more task based learning, but all the abstractions I need to clarify this are doing my head in

Much of your explanation makes great sense, and I'm so sorry to have wasted your time. You are an exceptional teacher and a fount of good solid knowledge, not to mention very patient with your explanations

Edited December 11, 2012 by Darklight

[Darklight]

Alchemica that textbook at Neuroscience online does look pretty awesome. I've bookmarked it and might give that a go instead in the new year

http://neuroscience.uth.tmc.edu/s1/index.htm

[Alchemica]

OMG Alchemica, thanks so much- I've spent the last two days looking at your response and trying to integrate what I can

Above all it's this which has made me decide to drop out of the course. If this is the level of confusion I get from the first 10% of the first week- and it was a slide from practically the beginning- I really can't see how I can finish the course

I think I'll just download all the week 2 lectures notes and videos and then sign out. It's a shame, but this is not a 4-6hr a week workload ( as advertised ) for me and is not the right time for me to dedicate the 20-30hrs I'd need to even come close to getting a grip

Damn shame they don't run these like apprenticeships, I'd happily become an apprentice and do more task based learning, but all the abstractions I need to clarify this are doing my head in

Much of your explanation makes great sense, and I'm so sorry to have wasted your time. You are an exceptional teacher and a fount of good solid knowledge, not to mention very patient with your explanations

 

Not a problem, even though you seem to give me more credit than deserved. It's good having someone rattle my shaky foundations with excellent questions. I'm glad if I can help you, as well as my own understanding

Hopefully you might have just jumped into more complicated matters than required - it would be good to have people finishing the course.

All the best.