This Is Your Brain On ...

[Gnosital]

Philboid Studge wrote

scathach, thanks for taking time out of a busy week to weigh in. The archaebacterium case inspired me to noodle around the internets a bit, and though I must confess I don't fully understand why this is puzzle, it is a fascinating topic.

Thanks, Phil! I am looking forward to being here more now that the quarter from hell is over.

Philboid Studge wrote

First, is it really true that “Voltage sensitive K+ channels were previously thought to exist only in animals that have a nervous system ...”? As an expert on ion channels -- expertise gained during my several minutes of learning what they are -- I’m finding that such channels seem to exist in almost every living cell. I gather that the archaebacterium in question is not unique for possessing K+ channels, but because it is conducive to x-ray crystallography and thus can be represented in high-resolution, molecular-level images (and so ion-channel function can be more directly analyzed). Roderick MacKinnon (a self-taught x-ray crystallographer!) did this en route to earning his half of a Nobel in chemistry in 2003).

Here's a link to the abstract from the paper I mentioned; http://www.nature.com/nature/journal...ture01473.html

The thing is, you are absolutely correct about there being ion channels in all living cells, however, the interesting thing about this archae (my noodling around on the internet larned me that the proper form of address for these critters among those in the know is now archae, because they aren't really bacteriums! http://www.ucmp.berkeley.edu/archaea/archaea.html Go figure!) is that it has a VOLTAGE SENSITIVE K+ channel, and those are the thingies they used to find only in eukaryotic cells. That is the cool part, because the channels are so structurally similar to those of neural cells that they actually respond functionally to the same toxins as those cells. The toxins appear to have specialized in the predators to inhibit the function of the voltage gated channels, which must have been around first, since the archae has them, but doesn't usually hang out near any scorpions or tarantulas.

Philboid Studge wrote

I have other, even denser, questions about this puzzle, but I want to be clear about my first question first. Please do not hold back on the scorn and derision in your reply; I have no feelings that need sparing. :|

Scorn and derision are not my style. Unless we're talking bout theists. I would gladly spank you if it would make you feel better though! :D

Philboid Studge wrote

Meanwhile: a few weeks ago, a company launched a “new personalized holistic 3 step Detox Therapy Program, which starts with a 10-30 minute foot massage from the Miracle Electro-Wave Foot Massager. Then a BBS ionic foot bath.” The purveyor of this hooey “recommends an herbal tea that will replenish the body and enhance the detoxification process. The tea is also supplemented with Raw Apple Cider Vinegar, Raw Honey and stevia to sweeten, ginger powder and liquid alkaline minerals.” I mention this New Age yip-yap only because it claims to be based on the very ion-channel discoveries of Dr. MacKinnon

Soooooo......... a foot bath is a detoxifier? I guess that might be the case if your python boot is too tight, and you can't get it off at night. Lotsa fucking assclowns are happy to toss around terms like "ion channels" without having the faintest idea what the hell they're talking about, just cause they're greedy lying bastards. "Liquid alkaline minerals" Jeebus H fucking christ on a crutch. (hey, I'd like to see that on a t-shirt!)

[Gnosital]

Phil, I don’t know if you’re interested, but I thought I’d throw together a little K+ channel primer for your perusal, edification and enjoyment.

Quotes are from my bible, Principles of Neural Science 4e (2000) Kandel, Schwartz & Jessell

Ion channels come in different varieties, and “most of the major classes of ion channels have now been cloned and sequenced” (p.116) and the DNA sequences have been used to model the secondary structures of the proteins. To understand the functions of these channels, various methods are used, such as patch clamp studies and single channel recording, genetic engineering of chimeric channels (creating channels with sequences substituted from different species, otherwise known outside neuroscience as “playing god” HEEHEEHEE), site-directed mutagenesis, and study of naturally occurring mutations and developmental changes in conductance across channels.

There are 3 gene-related families of ion channels, a) ligand-gated, b) gap junctions and c) selective channels including voltage gated and related subfamilies. The channels in each family “have similar amino acid sequences and transmembrane topology. Each family is thought to have evolved from a common ancestral gene by gene duplication and divergence.” (p.118)

Ligand gated means there is an extracellular site on the protein (this kind is also called a receptor-channel complex, and includes GABA and acetylcholine receptors) to which an endogenous or exogenous chemical substance may bind to either block or stimulate the conformational change that opens the ion channel. Lotsa drugs work on these puppies.

Gap junctions (connexons or electrical synapses) are not found in many places in vertebrate nervous systems, but are found in liver cells and heart cells and a few other places. These are hemichannels, one in the membrane of each of two adjacent cells that together form a kind of mutual tunnel through which there is free cytoplasmic flow between the cells. These are the sluts of the channel families, they let almost anything into their holes.

The ones we’re talking about in the archae that are also the most crucial to vertebrate nervous system function, are from the third family. These are channels selective for particular ions, and the K+ selective subfamilies include the following:

* voltage gated K+ channels (also called voltage sensitive or voltage dependent) channels, which undergo a conformational change when stimulated by changes in electrical potentials in the membrane. These are “composed of 4 polypeptide subunits…with 6 transmembrane segments and a loop through the extracellular face of the membrane (the so-called P region)” (p119). These channels are crucial to the generation of the action potential, carrying out re-hyperpolarization of the membrane following the depolarization caused by opening of voltage gated Na+ channels due to supra-threshold stimulation of the membrane.

* inward rectifying K+ channels (also called non-gated) “composed of 4 polypeptide subunits…(with) only 2 transmembrane segments, connected by a P-region loop” (p119). These channels play an important role in maintaining membrane resting potential, as they allow free flux of K+ across the membrane. Because there are more of these than non-gated sodium channels in the membrane, the resting potential of the cell (approximately –70mV) is closer to that of the equilibrium potential of K+ (approximately –90mV) than it is to the equilibrium potential of Na+ (+50mV). These are the channels MacKinnon characterized via high resolution X-ray crystallography. He used a K+ channel from an actual bacterium, not the archae. Apparently it’s difficult to get crystals from integral membrane proteins, and so the bacterium has an “inward rectifying type of K+ channels that are also present in higher organisms, including mammals. These channels have the advantage of having a relatively small size and simple transmembrane topology” (p 120).

* “Two pore domain K+ channels …(with) a characteristic subunit structure corresponding to 2 repeats of the inward rectifying K+ channel architecture, with 2 P-regions in tandem. The composition of these channels is not known.” (p119). I gather the function is not well understood either.


Tim, I didn’t know that anyone is trying to say this is evidence for the idea that the first life forms appeared at thermal ocean vents, but it does seem to make sense that if an archae has the voltage sensitive channels and mammals have the voltage sensitive channels, and that the sequencing is similar (which it is):

“…all voltage gated channels have a specific membrane spanning domain that contains positively charged amino acids (lysine or arginine) spaced at every third position along an alpha helix. This motif is observed in all voltage-gated channels, but not in transmitter gated channels…” (p117)

then it is parsimonious to interpret this as an example of a conserved rather than independently evolved structure. As you say, it is not possible to rule out that the channels independently evolved. Apparently there are huge numbers of channel subtypes in a multicellular species, e.g. in C. elegans “the genome contains 5 genes for voltage gated Ca+ channels, over 60 genes for K+ selective channels, 90 genes for ligand-gated channels, and 6 genes for Cl- selective channels” (p120). However, Ruta’s work seems to point toward the conserved structure interpretation. My thinking on the exaptation thing was a guess, since I have been too lazy to search for anything explaining the function of the voltage gated K+ channel in the archae. It doesn’t seem like it would be needed for action potential generation, as there is no nervous system. If anyone knows where to look for that info, I’d be ever so grateful if you’d share. Cause it’s time for me to go back to real work.

[Gnosital]

Kate wrote

Anger Management ... (British Solution)

Kate, that is hilarious. Next time some assclown in an SUV with a for sale sign tries to broadside me off the road, it's on.

[Tenspace]

I had a friend - we'll call him John - in Bham pulled something similar, but not nearly as inventive. He was cut off by a pickup truck with a For Sale sign and a phone number. A few days later, he called the guy, feigning interest in buying his truck. The meetup was set in the parking lot of an office building adjacent to my friend's office - he could see the parking lot from his window. The guy shows up about ten minutes early, and waits. John watches the guy, and watches. After about thirty minutes, the guy seems pissed enough and starts to leave. John calls him and tells him he's stuck in traffic and should be there in about fifteen minutes. The guy waits another thirty minutes. John calls him again as he's about to leave and tells him that he had a flat, and promises to be there in a few minutes. All the while, he's standing in his office watching this guy and laughing his ass off.

This went on for almost two hours before the guy finally figured out he had no buyer for his truck. That's when John called him back and let him know how impolite it is to cut people off.

[Kate]

:lol:

You two have been very naughty. I just use the "Dial 1-800-EAT-SHIT" bumpersticker. Good stories, though! I'll have to remember this tactic next time I'm cruisin' 85 in a 70 on the BeeLine (528 in Florida) and some turdburglar in a pickup has only the grille showing in my rearview mirror. That is, after I tap the decel button on my cruise control until I am turning only 69, and the driver roars around. :lol:

scathach wrote

Thanks, Phil! I am looking forward to being here more now that the quarter from hell is over.

Here's a link to the abstract from the paper I mentioned; http://www.nature.com/nature/journal...ture01473.html

The thing is, you are absolutely correct about there being ion channels in all living cells, however, the interesting thing about this archae (my noodling around on the internet larned me that the proper form of address for these critters among those in the know is now archae, because they aren't really bacteriums! http://www.ucmp.berkeley.edu/archaea/archaea.html Go figure!) is that it has a VOLTAGE SENSITIVE K+ channel, and those are the thingies they used to find only in eukaryotic cells. That is the cool part, because the channels are so structurally similar to those of neural cells that they actually respond functionally to the same toxins as those cells. The toxins appear to have specialized in the predators to inhibit the function of the voltage gated channels, which must have been around first, since the archae has them, but doesn't usually hang out near any scorpions or tarantulas.

Scorn and derision are not my style. Unless we're talking bout theists. I would gladly spank you if it would make you feel better though! :D

Soooooo......... a foot bath is a detoxifier? I guess that might be the case if your python boot is too tight, and you can't get it off at night. Lotsa fucking assclowns are happy to toss around terms like "ion channels" without having the faintest idea what the hell they're talking about, just cause they're greedy lying bastards. "Liquid alkaline minerals" Jeebus H fucking christ on a crutch. (hey, I'd like to see that on a t-shirt!)

Stinkfoot, stinkfoot, I ain't lyin', can you rinse if do you suppose? Here Fido, bring the slippers.....
Alas, poor Frank left us at the tender age of 50 due to prostate cancer, thus unable to enlighten us further with the dementia that was his style of music. :(

[Choobus]

Tenspace wrote

I had a friend - we'll call him John - in Bham pulled something similar, but not nearly as inventive. He was cut off by a pickup truck with a For Sale sign and a phone number. A few days later, he called the guy, feigning interest in buying his truck. The meetup was set in the parking lot of an office building adjacent to my friend's office - he could see the parking lot from his window. The guy shows up about ten minutes early, and waits. John watches the guy, and watches. After about thirty minutes, the guy seems pissed enough and starts to leave. John calls him and tells him he's stuck in traffic and should be there in about fifteen minutes. The guy waits another thirty minutes. John calls him again as he's about to leave and tells him that he had a flat, and promises to be there in a few minutes. All the while, he's standing in his office watching this guy and laughing his ass off.

This went on for almost two hours before the guy finally figured out he had no buyer for his truck. That's when John called him back and let him know how impolite it is to cut people off.

:lol::lol::lol:. We should all do this if we ever see a jesus fish car for sale. We can make christian themed excuses for not showing up.

[Sternwallow]

The good Lord laid a heavy spiritual burden on my heart and refuses to let me be seen in a [insert model of victim's car] as long as they are driven by obvious Christian assclowns.

[Philboid Studge]

Scat, Thanks much for the additional info. I'm going to take a closer look when I've put some work behind me this week. (I don't suppose you have the whole Nature article? I see one of the authors is MacKinnon; published in the year he won the Nobel)

Meanwhile, I cherish this image of you going on a rant while lecturing, scaring the crap out of your students: "Lotsa fucking assclowns are happy to toss around terms like "ion channels" without having the faintest idea what the hell they're talking about, just cause they're greedy lying bastards. "Liquid alkaline minerals" Jeebus H fucking christ on a crutch..." :)

[Gnosital]

Philboid Studge wrote

Scat, Thanks much for the additional info. I'm going to take a closer look when I've put some work behind me this week. (I don't suppose you have the whole Nature article? I see one of the authors is MacKinnon; published in the year he won the Nobel)

Sorry, I'm not one of their paying customers. I may request it on OHIOLink, but that could take months. I suppose I could go collect the article the old fashioned way......bleh! Maybe after the benedryl wears off. Too fuzzy to drive (or type) at the moment and thinking too hard would will harsh my buzzzzz...

Philboid Studge wrote

Meanwhile, I cherish this image of you going on a rant while lecturing, scaring the crap out of your students: "Lotsa fucking assclowns are happy to toss around terms like "ion channels" without having the faintest idea what the hell they're talking about, just cause they're greedy lying bastards. "Liquid alkaline minerals" Jeebus H fucking christ on a crutch..." :)

I've actually carried out a reasonable approximation of such a rant, sans the "fucking" and "jeebsu H....etc." parts. I do have a pretty sweet gig with my job (most days) so I'd like to keep it for a while.....

[Philboid Studge]

scathach wrote

That is the cool part, because the channels are so structurally similar to those of neural cells that they actually respond functionally to the same toxins as those cells. The toxins appear to have specialized in the predators to inhibit the function of the voltage gated channels, which must have been around first, since the archae has them, but doesn't usually hang out near any scorpions or tarantulas.

Scat, An obvious question about the toxins: They are peculiar to only these arachnids? Would the channels be susceptible to say, cone shell toxin? Not that cone shells are found near deep ocean vents -- as far as I know they're shallow-water, reef dwellers -- and certainly not in hot springs like those at Yellowstone (I've seen Obsidian Pool; the article you linked has a pic of a Berkeley biologist taking a whiz in it) -- but the seas are well-stocked with other toxic critters. It would be a somewhat less freakier puzzler than if only tarantula and scorpion juice were the gate inhibitors.

I see a (tenuous) analogy between this and the case of cannabinoid receptors -- which were found in the brain and the spinal cord in 1990. For a couple years, people wondered why the hell the brain would be equipped with receptors that seemed to serve no other purpose than react with delta-9 THC. But then the ligand anandamide was discovered (1992), the mystery solved. (Similarly, opiate receptors in the brain were discovered through opium and heroin use. After that discovery, the opoid-like chemicals produced in the body that control pain were discovered.) My point: setting aside the admittedly gaping holes in my analogy, in a couple more years of research, other functions of the K+ channels might be revealed; meanwhile they also happen to be inhibited by specific toxins.

This older Discover article (ten years is an eternity in this field!) gave me a little background:

"To begin with, [Susan Barns] identified a pair of archaea that are the most primitive organisms on Earth: their ribosomal RNA is very close to what the primordial ancestor of all archaea and eubacteria must have had. Barns thinks the lineage of her two new species can be traced to shortly after that primordial split, and that they have changed very little in the past 3.5 billion years. Her discovery of such venerable organisms in the Obsidian Pool lends further support to the notion that life may have begun in a hot spring, either on land or on the seafloor."

[Gnosital]

Phil, I know NOTHING about arachnid toxins. My guess on the channels is that there were likely simple integral membrane proteins that evolved specializations (and a few membrane spanning segments) through genetic mutations in the cleavage enzymes. The increased diversity in the protein sequences allowed for selection of more flexible channel reactions to environmental stimuli, and eventually produced a voltage gate specialization. The docking areas on the external portions of the channels would have a particular molecular configuration, which is how a toxin molecule could be selected for its effects on the organism, if it was similar in molecular configuration, the key fits the lock and hijacks the channel to its own evil/survival purposes. I’m completely talking out my ass here, because I’m not well versed on molecular genetics, so if you or anyone can clean that up, I’d be mightily obliged.

Anyhow, the cannabinoid/anandamide receptors are not a bad analogy at all. Just not toxic! Neither LSD nor THC has a reliably established LD50 (lethal dose for 50% of the dosed sample population). But nicotine and alcohol are both highly toxic (nicotine has an LD50 of 60mg, the amount in about 30 cigarettes or 2 cigars and alcohol something around BAC of 0.3 I think…) and yet, they’re legal. Why would this be so? Might it have something to do with inherent racism? Methods of sociological control? In-group out-group effect?

But I digress. As you say, cannabinoid receptors were characterized long before the endogenous ligand was discovered, and the fact that cannabinoids have central effects was the first clue to look for the mechanism of action. Then they found the receptors and lo and behold, they are most likely the most numerous receptors in the entire nervous system! There are CB receptors on nearly ALL cortical neurons, they appear to be even more numerous than GABA or glutamate receptors, which have been called the “workhorses” of the nervous system. The only place CB receptors are NOT found in abundance is in the medulla oblongata, which contains the neural structures responsible for stuff like respiration, heart rate, blood pressure regulation, digestion and other necessary-for-living type stuff. Hence the insanely low to non-existent lethality of the compound. But there ARE receptors for legal shit like nicotine, opiates, barbiturates, and benzodiazepines, and alcohol in those necessary-for-living parts of the medulla, and those receptors can kill ya if you aren’t careful with your dosing regimen.

WTF.

What was I talking about? Oh yeah, the only part of your analogy that may not work is that while the toxins may have been selected to allow one organism to benefit from another, I doubt that plant cannabinoids evolved to make humans happy. Maybe less a case of selective advantage and more a case of random independent evolutionary happenstance. But such random happenstance is probably not so random in that it may reveal something about the mysterious tendencies of protein folding during transcription and somebody should really be looking into it for a Nobel prize or something.

But then again, it might be jeebus that does it, it's just way too intricate and amazing.

[Philboid Studge]

Good stuff, Scat. Thanks. I've nibbled but will eat and digest later. "Mmmm ... cleavage enzymes"

Meanwhile, and slightly OT, I see from this week's Science News (picking up a current Nature article) a possible explanation of how the Earth stayed warm back in the day -- i.e., the Archaean era, 3.5 bya -- when the sun was putting lout less than 3/4 what it does today. Good old (very old) methane.

[Gnosital]

:lol::lol::lol:


So life and shit have always been intimately related. I knew it!