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GABA Receptors: Endogenous and Exogenous Ligands

Our bodies are composed of four basic tissue types: epithelial, muscular, connective, and nervous. Within nervous tissue, a dense web of 100 billion neurons (the functional unit of the nervous system) are constantly intercommunicating. This communication takes the form of both electrical and chemical signals. Perhaps the most simplified signaling essentially involves an on/off switch. In the nervous system, this takes the form of excitatory or inhibitory signals that alter the charge separation across a neuron’s membrane.

The membrane of a neuron typically has a charge separation of around -70 millivolts. That is to say, the interior of a resting cell contains negatively charged ions equaling around -70 millivolts. When communicating excitatory signals, we primarily use the amino acid glutamate. Inhibitory signals are typically communicated using gamma aminobutyric acid (GABA).

gaba1

GABA

Signaling molecules, such as GABA, can deliver their message by interacting with their receptor. As one may expect, GABA binds to GABA receptors, of which two main complexes have been detailed: GABAA and GABAB. GABAA receptors act as ion channels, whereas GABAB is coupled to a G protein that catalyses enzymatic reactions within the associated neuron. Both forms are well known pharmaceutical targets and will be the focus of this article.

Medications that utilize GABA pathways are said to be GABAergic. Such medications have a rich history in medicine and pharmacology as treatments for a variety of conditions, such as anxiety disorders, multiple forms of epilepsy, movement disorders, insomnia, and others. If any of these or any other conditions interest you, please leave me a comment and I will be happy to write a detailed article on how modern medicine approaches their treatment.

GABAA receptor channels are ubiquitous in the central nervous system and mediate an inhibitory response through their chloride ion permeability. Structurally, the GABAA receptor is composed of 5 transmembrane protein subunits with an interior ion channel pore. As such it is a pentameric protein with multiple subunits. The GABAA receptor’s pore functions as a ligand-gated ion channel, as the binding of its ligand GABA will catalyse rapid structural changes that permit the entry of chloride down its chemical gradient and into a cell. Chloride is a negative ion and an increase of negative electrical potential within a cell is said to “hyperpolarize” a cell. This often conveys an inhibitory function to the cell.

gaba2

Diagram of GABAA Receptor

Several important drugs modulate the GABAA receptor complex. Among these, perhaps the most well known are benzodiazepines, ethanol, and GHB. Their actions on the GABAA receptor complex are very detailed, likely owing to the heterogeneity of GABA receptors themselves. GABA receptor heterogeneity results from their numerous subunits: six α subunits, three β subunits, three γ subunits, three ρ subunits (building blocks of the formerly called GABAC receptors), and one each of the ϵ, δ, θ, and π subunits. Five subunits from 19 isoforms form a complex around a central ion channel.

As previously stated, GABA is the endogenous ligand for the GABA receptor. Thankfully, many exogenous ligands have also been discovered to interact with the GABA receptor. Research has identified several distinct binding sites on GABA receptors for exogenous ligands: GHB, picrotoxin, barbiturates, neuroactive steroids, benzodiazepine, ethanol, inhalation anesthetics, furosemide, and sites for various divalent cations such as Ca2+. Some of these sites likely overlap and interact, and probably more exist that have yet to be detailed.

Benzodiazepines have one of the more interesting and unique interactions with the GABA receptor. Classical benzodiazepines like valium (diazepam) act as positive allosteric modulators. The binding of a benzodiazepine to the GABA receptor causes a conformational change in the receptor. As such, they do not open the ion channel themselves, but act to increase GABA’s ability to bind the GABA receptor. This is known as increasing affinity of GABA for the GABA receptor. The duration of activity is also increased once a GABA receptor is activated by GABA in the presence of benzodiazepines. The effect of benzodiazepine-GABA receptor-interaction is known as positive allosteric modulation.

Ethanol is also involved in some interesting interactions with the GABA receptor. The specifics are still not absolut-ly everclear, but research does suggest that alcohol interacts with GABA receptors such that an influx of chloride ions occurs as though GABA itself has bound and activated the GABA receptor. Modern research also suggests that ethanol acts to increase the presynaptic release of GABA itself, flooding the synapse with GABA and thus activating far more GABA receptors in the presence of ethanol.

GHB interacts with GABA receptors in ways that mimic those of their endogenous ligand GABA. Predictably so, viewing the structure of GHB compared to GABA gives one the indication that they may engage in similar signaling functions. The molecular difference being that the gamma carbon on GHB contains a hydroxyl (-OH) functional group whereas in GABA the gamma carbon contains an amino (-NH2) functional group.

gaba3

One must remember that it is of extreme importance to never combine GHB and alcohol. This is a deadly combination and should not be attempted under any circumstances. The same goes for combining any GABA receptor-activating drugs. And, as always, if any of the above information is unclear please comment on this article as I am happy to clarify. I also appreciate any suggestions for future science-related articles. Thanks for reading :).

14 comments

  1. SantanaTheGreat

    Is it also deadly to combine benzodiazepines and GABA capsules?

    • Well, I don’t believe that consuming GABA orally has any effect. Likely it would be broken down in your stomach, or absorbed and converted into something else. The GABA or body utilizes at GABA receptor sites is very carefully regulated by the nervous system.

      Also, benzodiazepines are relatively safe. I don’t recall overdosing being a major issue, although they can become deadly when combined with other drugs (I’m looking at you, opiates). Hope this helps, thanks for reading and please use drugs carefully.

    • GABA on it’s own doesn’t penetrate the blood brain barrier in any important amount. And if you have 1kg of pure gaba it’s a waste to eat and not synth some ghb from it. It’s not as simple as gbl->ghb but not that hard either.

  2. Great article. I’d like to see an article on why the brain has receptors for nicotine, valium, benzos, and cannabis. Why are we born that way? What was the precedent? How does it work?

    • These are great questions, thank you.

      Benzodiazepines are positive allosteric modulators for the GABA receptor (as described here: /2016/06/06/gaba-receptors-endogenous-exogenous-ligands/). The GABA receptor is our body’s main way of sending inhibitory signals (relaxation). Benzodiazepines hijack this function, as many medications do for their respective receptor system. I really make an attempt to address your questions in the context of the GABA receptor in the other article linked above.

      Regarding cannabinoid receptors, the drug was known long before we identified its receptor. As such, receptors for cannabis are named after cannabis itself (Cannabinoid receptors 1 and 2 or CB1 and CB2). They are G protein coupled receptors. These receptors are normally bound by the endogenous ligand known as “anandamides.” Predictably so, I believe these are involved in regulating hunger and sleepiness or something (I haven’t researched them very much, but would be happy to do so in the future for an article).

      I do recall learning that the mechanism of action for cannabinoids is rather unique, it involves retrograde signaling. this is so unique in fact that its publishing was delayed for quite a while as researchers couldn’t believe the results. It’s a very interesting bit of history, although I’m a nerd and really enjoy learning about the history of science.

      Another family of medications with well-researched receptors are the opiates/opioids. These bind to opioid receptors that are normally utilized by the endogenous ligands endorphine, enkephalin, substance P, and others.

      Thanks for reading, and thanks for the great questions. Hope this helped.

    • Oh wow, I just realized that I linked to this article when replying to your article. Wow I’m a fool, sorry about that. I also can’t seem to alter it as it hasn’t shown up yet, I’m not sure why.

  3. What receptors does ketamine work with ?

    • ImNotAScientist

      The hallucinogenic dissociative effect comes from antagonism of NMDA receptors. Most dissociatives also agonize dopamin receptors, some also agonize serotonin or opioid receptors. The most famous dissociatives (Ketamine, MXE, 3-MeO-PCP) are derivates of PCP, but there are also atypical opioids with hallucinogenic dissociative effects, like MT-45, Dextromethorphan, or the Salvia Divinorum plant (which is the only existing natural dissociative). From all dissociatives, PCP has the highest affinity to dopamin receptors (which is where the madness comes from), Salvia to opioid receptors, MXE to serotonin receptors (can’t provide source). Serotonin, Dopamin, and some of the opioid receptors have hallucinogenic properties, but the antagonism of NMDA receptors is where the magical dissociatiation comes from.

      • Great answer, thank you. You should write an article about the NDMA receptor and dissociatives, I’d enjoy reading it. I did a little research on the NMDA receptor and remember reading about how PCP has a rather unique binding characteristic. Something about how it binds a location within the NMDA receptor channel, forming an actual physical plug. Very interesting stuff :)

        I feel it’s important to also mention that the possibly psychotic/dangerous dopaminergic affects of dissociates (think PCP) are rare. This is because the receptor affinity of these dissociatives for the dopamine receptor is very low.

        You only tend to see them when someone has taken waaaay too much.

      • That’s not entirely true. Just sticking to some of the more well known achs, both tcp and bdtcp are stronger ndris than pcp.

  4. This is just a test, I’m not sure why my replies aren’t showing up. Hopefully they do soon. Thanks for reading!

  5. Kevin, you’re doing great job! Thanks for this article, I hope there will be more! Basics of physiology, biochemistry, psychiatry and all medical sciences should be spread all around the internet :)

    • Brazil

      @Joe Shmoe
      You show your ignorance and ideology by claiming psychiatry as a science. It has nothing to do with the scientific method at all, corresponding in no way to any structures within the brain. Why do you wish to spread a totalitarian pseudo-science “all around the internet”? How do you make your money?

  6. Do something more in depth please. Which gabaa subtypes are responsible for what, which benzos bind/activate which subtypes more strongly (if you can dig up a table with actual affinities and predicted affinities for those that were never measured that would be awesome), reasons why some have longer half lifes than others, how they are metabolised, fast quite of what to look for in the structure for desired effects (R2′ fluorine -> increased potency and hypnotic effects, chlorine -> even more potency, less hypnotic, …

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