Mapping the Glutamate Receptor

So Sci said she wasn’t going to blog this week because of Open Lab and how stressed she is.
(Sci right now, only with better hair and no pocket-protector)
But she lied.
The science, it calls us, precious.
Ah, the power of Twitter. It is indeed powerful, for it hath informed Sci of a new development in SCIENCE. Also, it made her sing. We’ll get to that. Sobolevsky, Rosconi, Gouaux “X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor” Nature, 2009.
glutamate receptor.jpg
Pretty, huh?

So, as you can see from the title and from the picture, the authors of the paper managed to crystalize and map out one of the glutamate receptors, the GluA2. And I’m sure a bunch of you are sitting around and going, “very pretty, but who cares?” Answer: a lot of neuroscientists care. Also, you care. Or at least you will, once you know what it’s all about.
As you might guess from the name, glutamate receptors are receptors for the neurotransmitter glutamate. As a brief review of neurotransmission (I’ve written a big post on this before), a neurotransmitter, which is just a chemical of a particular type, in this case glutamate, is released from little sacks, or vesicles, inside a neuron. It floats across the space between two neurons (called the synapse), and binds to receptors on the other side. The type of receptor it binds to will determine how the cell on the other side reacts, whether it propagates a signal like an action potential, or is stimulated to release a hormone. The whole thing, in picture form, looks a little like this:
glutamate synapse.jpg
So this is all well and good. We know the basics, that glutamate (the neurotransmitter of choice in this case) binds to these receptors, and that this binding will cause a change in the receptor, and cause something to happen. What happens when a receptor is stimulated like this depends on the type of receptor involved. For example, there are two major types of glutamate receptors. These are ionotropic and metabotropic. Ionotropic receptors are receptors that, when you hit them with glutamate, change conformation and open up an ion channel, allowing ions to pass through, and changing the inner charge of the cell that way. This change in charge can do things like pass on an action potential. The other kind of receptor is called a metabotropic receptor, and these are MUCH more complicated. They involve something called a second-messenger system, which is something Sci will really have to blog about when she has a lot of time on her hands and is feeling somewhat sassy. But for now, suffice it to say that they are really complicated, and can do a truly vast number of things. For now, we’re concentrating on the ionotropic version.
For it was the ionotropic version that they figured out the structure of in this paper.
glutamate receptor2.jpg
Here’s another picture. You can see the whole structure on the top left, and top down view on the bottom right. The receptor (GluA2) is made up of four subunits (represented here in different colors which makes Sci think of delicious rock candy), and the middle (which is blown up large on the center left) makes up the ion pore, through which the ions will go when the receptor is open. Also, note the bottom section with all the curlicues. Those are arrangements of amino acids known as alpha helices, and where they all bunch together like that is where the receptor holds tight to the cell membrane. The rest of the stuff sticks up outside it.
Now, you might think “woo! We got the ionotropic receptor! That means we’ve got half the glutamate system done, right?” Well, wrong. There are…11 glutamate receptor subtypes at least. But the GOOD news is that a lot of the ionotropic ones are made up of patterns of the same subunits that are mapped here, meaning that we now have a lot more clues as to how to put other similar receptors together. This paper has opened up a lot of new doors into the glutamate receptor world, even if that world still seems…really really complicated.
And so, you might say, well that was nice. But what’s it FOR!?
Glutamate (also called glutamic acid, it’s one of the salts) is one of the most important neurotransmitters in the brain. It is known as the main excitatory neurotransmitter, meaning that it promotes neuronal activity. It is one of the most abundant neurotransmitters in the central nervous system. This means it plays a role in a lot of very important things. Glutamate is known to be involved in things like seizures, as well as in diseases such as schizophrenia, and it probably plays a role in other disorders of neurotransmission, like Parkinson’s, Huntington’s, depression, anxiety, and other disorders. As far as drugs go, PCP and ketamine (the veterinary anesthetic that is apparently also abused) acts on glutamate receptors as well.
So knowing the glutamate receptor could be very useful down the line, for formulations of new pharmacotherapies to treat different disorders. If you know the structure of a receptor, you can figure out how it can be changed, how it can be activated, and how it can be blocked. So mastering the structure of the glutamate receptor could open the door to a lot of important discoveries and treatments for diseases.
And now we get to the part that made Sci sing. Because while mapping the GluA2 was a massive undertaking, and very very important, there are lots more receptors to go. And so I sing, I WANT THE WORLD!!!

Sci wants the world
Sci wants the WHOLE WORLD
Sci wants her GluR1,
Glur2A is done,
Where is her GluR1!
Give it to me, NOW!
Sci wants it all
A receptor Party!
Ionotropics new
Metabotropics, too!
Give it to me, NOW!
I want the works
I want the whole works
Receptor maps of all shapes and sizes
Binding site surprises!
And now!
Don’t care how!
Sure as heck don’t want to map it myself…
I want it now!!
Sobolevsky AI, Rosconi MP, & Gouaux E (2009). X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature PMID: 19946266

11 Responses

  1. Very entertaining! elucidation, pretty diagrams AND a song!

  2. Sci, I had that song in my head ALL DAY Monday thanks to your Twitter-singing (twinging??). Looks like my lab-mates are in for another serenade today…love the new verses!

  3. First off, I just started reading your blog and I love it. Secondly, my minuscule knowledge of glutamate is that it is the most active neurotransmitter during learning and that the production and reception of glutamate is greatly increased by calcium. From this I have concluded that the best brain food is milk and cookies and and am now in the process of convincing my roommates to shift our diet to just that. They are skeptical and think ice cream would be more efficient ;).

  4. Brilliant and entertaining elucidation as usual, Sci.
    Although I gotta say, “Glutamate” sounds like a euphemism for anal sex 😀

  5. Awesome. So we have those cute little things in your braincells. Mh.. yummy.

  6. Dr. Becca: MWAH-HA-HA-HA!!!!
    Jeff: An excellent idea! I highly encourage further consumption of ice cream in everyone’s daily life.
    Arvind: um…ew.

  7. Dr. Becca: MWAH-HA-HA-HA!!!!
    Jeff: An excellent idea! I highly encourage further consumption of ice cream in everyone’s daily life.
    Arvind: um…ew.

  8. Aw, c’mon! Glutes? Mate? Never mind…It’s horrid indeed…(slinking off)

  9. Pretty! Looks like Christmas ribbon curls.

  10. Ketamine has also been used as an experimental treatment for depression.
    I want the NRs, I want all six…

  11. Nice piece of work, for sure! However, it seems to me that it shouldn’t be of such great help for the disease you mention: it’s a bit like learning about quantum electronics for designing better cars. It’s surely a fundamental thing to know about, maybe even to design faster electronic circuits but way to fundamental (and ubiquitous) to really help in most challenges faced by automotive design.
    My guess is that any pathology affecting this receptor would affect so many functions of the brain that it should be devastating for **all** aspects of cognition (perception, movement, emotions, etc.) which is far from what is the condition of most psychiatric diseases where many many brain functions are nonetheless preserved.

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