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GABAergic binding sites - sorting it all out

bindingaffinity

bindingaffinity

Bluelighter
Joined
Apr 19, 2012
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150
Ok folks, so lately I've been trying to learn more about GABA-A receptors and their pharmacology. From what I've read, it seems like there are at least 4 main binding sites:

  • binding site of GABA itself, also targeted by muscimol and gaboxadol
  • barbiturate/picrotoxin binding site
  • benzodiazepine/flumazenil/DBI binding site
  • etomidate (& analogues)/methaqualone (& analogues)/loreclezole binding site
Does this seem correct overall? Are there any major binding sites that I'm missing?

There are a number of other questions I have about other GABA-A ligands, such as:
  • which binding site is targeted by ethanol and other alcohols? (e.g., trichloroethanol, ethchlorvynol, chloroform, 2M2B...)
  • do subtype-specific GABA-A ligands such as zolpidem bind to a different site than benzodiazepines? or does the affinity of ligands for that site vary widely based on the subtypes of the given receptor?
  • how (if at all) do GABA analogues such as pregabalin, gabapentin, and valproic acid interact with GABA receptors?
  • have the atypical psychedelic/deliriant actions of muscimol been pharmacologically explained? how about zolpidem?
  • in the doses used in ayahuasca and changa, do beta-carboline alkaloids manifest any effects caused by GABA-A interaction, or are they acting solely as MAO inhibitors?
I'd appreciate it if anyone knows the answer to, well, really any of these questions.
 
About the first part of your question: I think this is a misunderstanding. I think that the GABAA receptor doesn't have binding sites as such, there are just drugs that happen to bind at certain 'places'.

Did you read the wikipedia article ? There is a nice picture, but it doesn't show the binding place of the barbiturates.
 
Wiki says, "The active site of the GABAA receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline.[citation needed] The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly." IUPHAR's paper on classification and terminology also calls them "binding sites". I think there may just be a difference in terminology.
 
Alcohol's binding site isn't entirely clear because apparently alcohols stick to cell membranes and are therefore difficult to do radioligand studies with. But there is a ligand Ro15-4513 that is probably interacting with the same site as alcohol (there is a competitive interaction). http://m.pnas.org/content/103/22/8546.full
 
The ´binding sites´ are simply ´places where a drug binds to´. It is not as if there are distinct ´natural´ sites that were waiting for the discovery of certain drugs.
There is that protein, and some drugs happen to bind to it at certain places or ways. Benzodiazepines are drugs that are capable of mutilating the GABAA receptor.
 
Kdem, thanks for the clarification. I see what you're getting at now. Didn't intend to imply that these sites have endogenous ligands or that the proteins evolved to bind to anything at those regions... just using the terminology I had heard in papers.
 
Cotcha Yankinov, thanks for linking that article. I found a couple interesting follow ups about that receptor and alcohol sensitivity. I've only skimmed them but one of them mentions "evidence that alcohol effects are influenced, or even partly mediated, by GABA-active endogenous neurosteroids", which is really intriguing. I'll have to look into that; forgot to mention neurosteroids in my original rundown. Second article proposes that ethanol binds to the α+β− subunit interface in αβ₃δ receptors; interesting contrast to the proposed β+α− methaqualone/etomidate site at α(1,2,3,5)β(2,3)γ(2S) receptors (probably just a coincidence).
 
Benzodiazepines are drugs that are capable of mutilating the GABAA receptor
Click to expand...

The way benzodiazepines increase neurotransmission via GABA-A receptors is by binding to allosteric site and changing the conformation of the GABA-A receptor so that GABA can bind more effectively at the GABA site (the main active site of the receptor). They don't really mutilate GABA-A receptors. If you mean tolerance as a result of dependence, well, tolerance to drug effects is a common phenomenon for many drugs acting on different unrelated receptors as a counter-response of central nervous system and it is not limited to structural changes in the receptor, however, such structural changes are not directly a result of the ligand binding to receptors. Old receptors are constantly being replaced by new ones, so if there is any structural change, it is the change in newly formed receptors that matters, ligands can't damage receptors by reversibly binding to them, by binding irreversibly to a receptor, they just happen to be the last ligand to be bound, after that the receptor gets destroyed along with the ligand bound but such irreversible binding doesn't translate to real damage to the whole receptor system. Upon activation of a receptor downstream effects follow, at any point in the downstream there may be a mechanism responsible for decreasing response to the signal from the upstream, e.g. activation of receptor X by the first messenger (may be external ligand) causes release of the second messenger, this effect may be weakened as a result of tolerance even though there may be no real change in the affinity of the first messenger at the binding site. A real example of a counter-response in case of tolerance to benzodiazepines is increased release of glutamate to compensate for inhibitive effects caused by overactivity of GABA receptors. In short, tolerance to benzodiazepines and paradoxical effects appearing after long-term dependence are controlled by multiple mechanisms.

I can't explain it better as I'm not a professional in the field, but I hope at least it makes sense.

Here's a review article on the mechanisms responsible for tolerance to benzodiazepines after long-term use:
Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?
 
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Unfortunately I don´t have the sources at hand that I had in mind, I´d have to dig for that. Quickly googling the subject didn´t yield much.

Benzodiazepines bind to certain combinations of alpha, beta and gamma subunits. After long term use, the beta and gamma subunits can ´come back´ in different types.
I´m not sure if this one is exactly the same as the one adder provided, but it states something about the GABAA receptor in section 4.2. https://www.hindawi.com/journals/aps/2012/416864/
 
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