The central nervous system uses chemical messages to transmit information between nerve cells. One of these messengers is Gamma-aminobutyric acid (GABA), which functions as the primary inhibitory neurotransmitter by reducing the tendency of neurons to fire. This action is necessary for maintaining a stable neurological environment. To exert its effects, GABA must bind to specialized proteins on the surface of neurons called receptors, which recognize GABA and initiate a response within the cell.
Understanding the GABA Neurotransmitter System
When a neuron releases GABA into the synapse, the space between nerve cells, it binds to a GABA receptor on a neighboring neuron. This binding event causes the receptor, an ion channel, to open and allow negatively charged chloride ions to flow into the cell. This influx of negative charge makes the neuron hyperpolarized. This means its internal electrical state becomes more negative and further from the threshold required to fire an action potential.
This inhibitory action produces a calming or stabilizing effect on the brain. The balance between GABA’s inhibitory signals and excitatory signals from other neurotransmitters, like glutamate, allows for proper brain function. The effects of GABA are not uniform because it interacts with a diverse family of receptors. These receptors are classified into different types based on their structure and function, allowing the GABA system to tune inhibition in various brain regions.
Defining GABA C Receptors
Among the family of GABA receptors, one group is distinguished by its unique molecular structure. Historically identified as GABA C receptors, these proteins are ligand-gated ion channels constructed from protein subunits known as rho (ρ). Three rho subunits have been identified in humans: ρ1, ρ2, and ρ3. These subunits assemble in groups of five to form a functional receptor with a central pore through which ions can pass.
The composition of these five subunits can vary. Receptors can be formed from five identical rho subunits, a structure referred to as homo-oligomeric. They can also be formed by a combination of different rho subunit types, creating a hetero-oligomeric assembly. This ability to mix and match subunits allows for variations in the receptor’s properties.
GABA C Receptor Location and Core Functions
GABA C receptors are found in several brain areas, including the superior colliculus, cerebellum, and hippocampus, but are most prominently expressed in the vertebrate retina. Within the retina, these receptors play a part in processing visual information. They are densely located on the axon terminals of bipolar cells, which are neurons that connect photoreceptors to ganglion cells. These receptors help modulate and refine visual signals as they are transmitted through the retinal circuitry.
Functionally, GABA C receptors are chloride channels that have distinct operational kinetics. They are characterized by a high sensitivity to GABA, meaning they can be activated by very low concentrations of the neurotransmitter. Their response to GABA is also marked by a slow onset and offset, resulting in a sustained inhibitory signal that can last for tens of seconds. This sustained activity is among the slowest of all known ligand-gated ion channels and provides a form of long-lasting, tonic inhibition.
Unique Drug Interactions with GABA C Receptors
A defining feature of GABA C receptors is their pharmacological profile, which sets them apart from other GABA receptor types. They are insensitive to a range of drugs that modulate GABA A receptors. For instance, compounds like benzodiazepines and barbiturates, which enhance the activity of most GABA A receptors, have no effect on GABA C receptors. They are also not blocked by bicuculline, an antagonist used in research to block GABA A receptors.
These receptors are also unaffected by drugs that target GABA B receptors, such as the agonist baclofen or the antagonist saclofen. This pharmacological insensitivity makes them a distinct target for study. While they are blocked by the general chloride channel blocker picrotoxin, more selective compounds have been developed. An antagonist known as TPMPA has been identified as a selective blocker for GABA C receptors, providing researchers with a tool to isolate their activity.
GABA C Receptors Within the GABA Receptor Family
The classification of GABA receptors has evolved with our understanding of their molecular biology. Due to the structural relationship between the rho subunits and the subunits that form GABA A receptors, GABA C receptors are now classified as a specialized subset of the GABA A receptor family. In this modern nomenclature, they are referred to as GABA A-rho (GABA A-ρ) receptors. This reclassification acknowledges their structural heritage while recognizing their unique functional and pharmacological properties.
This places them alongside the fast-acting ionotropic GABA A receptors and the slower, metabotropic GABA B receptors, which use a G-protein to exert their effects. The diversity within the GABA A-rho subfamily is enhanced by the different possible combinations of the ρ1, ρ2, and ρ3 subunits. Genetic processes like alternative splicing, where a single gene can code for multiple protein variants, can also create different forms of the rho subunits. This adds another layer of complexity and functional variation to these inhibitory receptors.