Posted by chemist on June 19, 2004, at 15:00:17
In reply to Re: GABA » chemist, posted by Larry Hoover on June 19, 2004, at 7:57:20
> > hello there, chemist here... lar is spot-on. the entire question is quite moot, really: gamma butyric acid is water-soluble and lipid soluble, so crossing the BBB is not an issue. what is an issue is activating the GABA_{A} receptor and inducing chloride flux. if you take GABA and it works - as lar has said - then great. otherwise, there really is no need to go for it, as your GABA_A} (mostly) receptor needs to be inhibited by reuptake, so any additional flooding is not going to help unless you have a drug in the binding site that will inhibit...all the best, chemist
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> Dude, you raised more questions.
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> Both niacinamide and magnesium ions have been shown to increase GABA-ergic activity (my perhaps not totally correct/concise description). Do either/both of these qualify as "drug in the binding site"? I know both bind to the receptor, but not at the benzo site.
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> And that other point, about flooding. You're really saying that chronic dosing with oral GABA will not be as effective as taking it in pulses?
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> Thanks.
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> Lar
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>
the deal with niacinamide and magnesium is that they are important for conformational changes of the C-loop, which is at the ``bottom'' of the ligand-gated ion channel. niacinamide will bind between the alpha and beta sububits, but not at the BZ site, as you state. the other player is calcium, which was co-crystallized with AChBP homopentameric alpha_{7} (Brejc et al, Nature, 2001). the cations are not near the binding site(s); niacinamide qualifies as a ``drug bound in a ligand binding domain,'' but again, it's not the BZ site. as for taking GABA orally to increase concentration - i use the term flooding, as it''s the best way i think about it - i think there are too many variables that come into play before the rubber hits the road. first off, the pKa of the acidic proton is going to be above that of the GI juices, but not significantly so, so i suspect you have the neutral and deprotonated GABA before it hits your liver, at which point is there deamination or decarboxylation? i don't know, but assumming actual neutral GABA makes it into the noggin, you now have increased [GABA] (assume activity coefficient = 1). so, if now more GABA needs to be ``turned around,'' and this is going to keep [GABA] in the synape high, as only so much can be brought back into the fold/degraded. so what i am getting at is that chronic extra GABA introduced not by agonism of GABA_{A} (by a BZ) leads to desensatization. i would think acute dosing would be more effective and not lead to ``poop-out,'' same deal with ssris, except dopamine is implicated, and serotonin receptors (some) are structurally homologous with the LGICs like GABA and AChBP.....any of this jibe with your take? chemist
poster:chemist
thread:357170
URL: http://www.dr-bob.org/babble/alter/20040613/msgs/358133.html