NMDA receptors and hypoxia

(Note to my regular readers: A while back I toyed with the idea of starting a science blog, where I'd muse about the scientific questions and problems that float around in my head. I quickly realized that I do not have time to keep up a new blog, and given the infrequency with which I post to this one, I figured I could just kill two birds with one stone, and publish the occasional geekiness. If this post makes your eyes glaze over, I apologize.)

My scientific interests are pretty far-flung; I'm getting my bachelor's degree in Cellular, Molecular and Developmental biology this June, but I'm also interested in biochemistry, biophysics and physical chemistry, and neuroscience (from ion channels to systems neuro to the nature of consciousness). I read a lot for fun; today, I'm reading Hypoxia Enhances S-Nitrosylation-Mediated NMDA Receptor Inhibition via a Thiol Oxygen Sensor Motif, by Hiroto Takahashi et al down at UCSD, published in the January 4 issue of Neuron. Hypoxia is another of my random interests; any of you who have heard about my experience last summer on White Mountain know that. That said, this paper isn't exactly about high-altitude physiology, it's about the brain's mechanisms for protecting neurons in the hypoxic conditions that come about during stroke. in hypoxic conditions, it is logical that a system would want to attenuate NMDA receptor activity. Why is that, you ask?

NMDA receptors are one of the brain's types of glutamate receptors; glutamate, though it's less well-known than some other neurotransmitters, like dopamine or serotonin, is actually the central nervous system's major excitatory transmitter. The NMDA receptor has been extensively studied as a model for other neurotransmitter receptors; it's one of the best-characterized of the ligand-gated ion channels. It's also expressed in almost every region of the brain, indicating global importance in CNS function.

So why would the brain want to shut down NMDA receptors during hypoxic conditions? Consider that molecular O2 is absolutely necessary for brain function, but it also creates an oxidizing environment, leading to free radicals that can damage proteins and cause brain damage. The brain thus keeps its oxygen levels carefully rationed and controlled. PO2 in ambient air is around 140 mmHg; pO2 in the brain is closer to 10 mmHg. So there's very little room for error; O2 use must be controlled. In stroke, regions of the brain are cut off from the blood supply and thus have limited O2 resources. Oxygen is critical for ATP formation; ATP is consumed by the Na/K ATPase, or sodium/potassium pump, the membrane ion transporter responsible for establishing the transmembrane potential that is required for all ion flux and thus any neural activity whatsoever. NMDA receptors are ligand-gated ion channels; they create a path for ions to move down the concentration gradient established by the pump, thus requiring more ATP to re-establish the gradient and allow for further neural activity. If oxygen supplies are low, ATP cannot be produced in excess, and so the ion concentration gradient must be preserved in order for neurons to survive. It's a bit like how when the power is out, you keep the refrigerator door shut, unless you want all your food to spoil. It takes energy to establish the gradient (in this case, electricity establishes a temperature gradient across the door of the refrigerator), and by creating a path for the transfer from one side to the other, you destroy the gradient.

So what did Takahashi et al discover? They knew from previous work that there was a pair of cysteine residues in the NMDA receptor structure that formed a disulfide bridge under oxidizing conditions, but existed in a dithiol form under reducing conditions. So they solved the crystal structure of this part of the protein, and studied it under nitrosylating conditions, and discovered that the dithiol can be nitrosylated, but that in and of itself does not inhibit the enzyme. However, nitrosylating these two cysteine residues does make another cysteine residue more prone to nitrosylation as well, and it is this third site that actually inhibits the enzyme.

Interesting paper - I love to see structural biology tied in with ion channel physiology. It's also interesting to learn more about the importance of nitric oxide (NO) in short-range, short-term neural signalling. Considering that 20 years ago, we thought that NO was just a component of pollution, we have come to discover that it is critically important for everything from regulating blood pressure to neurotransmission.


osashiburi ne.

insert standard been-a-long-time apology, swear to blog more from now on, blah blah. i know, i know, heard it all before. what can i say? i have more important things to do, it seems, than blog. and i've been keeping a paper journal for the majority of the last year, one that's actually consumed one notebook and is doing serious damage to another. i find it cathartic; the fact that none of you out there on the Internets can read it means that i can write whatever the fuck i want without judgement. which is nice. but it doesn't do you, Dear Reader, any good, if you've just thought, "gee, i wonder how kat is doing" and surf over to my blog and i haven't written anything in months.

it's been a wacky year, that's for sure. 2007 has some great stuff in store, though, i am sure. one thing that's weird: i have a crush on someone. like, a giddy, goofy, secret crush that no one knows about but i've had for months. (okay, a few people know, but it's a closely guarded secret.) and i dare not say more than this, but... man! it feels good to actually *feel* something for someone..... even if it's someone i see less than once a week.

graduation: it's finally within my grasp. only 135 days left... until i will no longer be a damn undergrad. fuck! i need to figure out what i'm going to do after that. i have ideas, plans; as of yet, nothing concrete. need to start kissing professor ass.

been reading: lots of biochem. yesterday in lecture, i was the only one who knew the answer to a question the professor asked; i don't think he could see who it was who answered, but i nailed it and no one else was speaking up. that's my M.O. - i know the answer immediately, but i always wait at least a moment or two before i speak up, to let anyone else who knows have a chance. but today, the prof asked the question (what cofactor do amino acid decarboxylases use) and no one answered, he went on to the next slide, then asked if anyone had come up with an answer. so i said fuck it, and in a confident voice, "pyridoxal phosphate." ding! score one for me. yes i am a super lame dorkface, and everyone in all my classes secretly wants me dead.

been listening: the arcade fire. both funeral and the ep. how had i not really heard this band before, despite having heard them tons of times? also, the new shins album. just got it off of itunes, and am on my third or fourth listen... and it's good. it's really good. i really like the track "sea legs" - it's got a killer breakbeat (what?) and makes me wanna dance. and the rest of the album is great as well. obviously the shins are a band we can trust. i need to get my hands on a copy of oh, inverted world... it's the only one i don't have.

been watching: buffy. hardcore. (when i'm not studying.) (god, i'm a doublenerd!) i'm on season 6, and buffy is not so thrilled about being alive. but this is the season where buffy and spike get together, and let's face it: spike is the best damn character on the show. also just started angel - i've watched the first 3 episodes so far. it's pretty good, but my tolerance for david boreanaz angel is low. (i have nothing against the actor per se, just the broody character grates on me after too long.) but i am digging the comic-book-action-hero vibe... it's a different world than buffy's world, and angel has some sweet tricks up his sleeve (literally). and, spike. i love spike.

at risk of sounding even geekier (is that humanly possible?), and while i'm on the subject of television shows, if you're reading this and (BSG SPOILER ALERT) you are NOT on the edge of your seat wondering if a certain* fighter jock is actually one of the final five cylon models, (END SPOILER) you should be watching Battlestar Galactica. i've said it over and over again, but BSG is THE best show on TV right now. start with the miniseries from 2003, then watch the first season and you'll be hooked. it is smart, sexy, action-packed, full of intrigue, and just an all-around awesome show. give in, geeky is sexy anyway.

right-o. back to... microbiology prelab. (lab classes are pain-in-the-ass-y, but they're a necessary component of my education... or something.) leave me comments; it makes me more inclined to blog.

*extremely sexy


new pictures

new pictures up on my flickr site - i know, it's been forever. i've been taking mad pics, but not having internet at home* cripples my ability to upload them.

me and my little bear-kitty. :)

oh, also: just wanted to send out a teeny bit of condolence towards jared and tessa for the loss of their kitties. not TOO much condolence, mind you, since i still Officially Dislike both of them**, but maxwell and edward used to be my kitties too, so i'm sorry they're gone.

*do i mention this in every post? i think i do. i should shut up and order the intarweb, shouldn't i?

**though this might expire in a few weeks - i find it hard to hold a grudge for more than a year, especially when i am So Over it all. whatev.


suddenly it's 2007.

so it's been awhile... and it's a new year, and i completely missed a whole month of blog-posting. ah well. today marks the start of winter quarter, and i'm taking a full(er) load (than last quarter) - 3 real classes (2 lectures, 1 lab) plus research. whee.

maybe i'll start posting more once i break down and buy the internet. i think i might be able to squeeze a clearwire subscription into my monthly budget... but i'm delaying so i can think about it some more. especially since i want to upgrade to a more expensive phone plan (and give cingular the big fuck-you).