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).



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.


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.


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 :).

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