GABA receptors are located in the nervous system and bind to the neurotransmitter γ-aminobutyric acid. By binding, they exhibit inhibitory effects on neurons. The targeted administration of certain drugs can influence the receptors and thus also the nerve cells, which is relevant, for example, to the therapy of epilepsy.
What is a GABA receptor?
Receptors are sensory cells to which certain stimuli can bind. In perceptual structures, for example, receptors are the first instance of any perception. However, these structures also play an important role in many other bodily processes. The human nervous system, for example, is equipped with GABA receptors. The so-called neurotransmitters bind to these receptors. These substances are neurogenically active substances and thus correspond to messenger substances. The binding of the messenger substances to a GABA receptor has an inhibitory effect on the associated nerve cell. A distinction is made between ionotropic and metabotropic GABA receptors. The ionotropic binding sites include, in addition to the GABAA receptor, primarily the GABAC receptor. A metabotropic receptor is the GABAB receptor. The exact mode of action of GABA receptors depends on the particular subgroup. The ionotropic variants are ligand-gated and accordingly act on ion and electrolyte balance. For example, ion influx within a signaling cascade occurs through the activation of ionotropic GABA receptors. Metabotropic receptors act on metabolic processes and, after stimulus binding, activate the formation of secondary messenger substances within the signaling cascade.
Anatomy and structure
All GABA receptors in the human nervous system are located on one neuron each. Each of the receptors is a so-called transmembrane protein. Transmembrane proteins correspond to integral membrane proteins with one or more transmembrane domains. A transmembrane domain is the lipid bilayer that spans integral membrane proteins. Receptors are equipped with structures to which certain substances can bind. Due to the fixed structure of their binding sites, all GABA receptors react exclusively to specific influences and are thus only capable of binding to specific messenger substances or neurotransmitters. The receptors specifically bind primarily the neurotransmitter γ-aminobutyric acid. The GABAB receptor, unlike the other subgroups of GABA, is a G protein-coupled receptor that can be located both pre- and postsynaptically. GABAA receptors correspond to ligand-activated ion channels that are permeable to hydrogen and chloride carbonate ions. They are heteropentamers and thus each consist of five subunits, each spanning the cell membrane four times. Homologous subunits are the six α1 to α6 representatives, the three β1 to β3 representatives, the three γ1 to γ3 representatives, and δ, ε, π, or θ with one representative each. ρ has three representatives from ρ1 to ρ3. In the brain, receptors are mostly composed of two α- as well as two β- and one γ-subunit. GABAA receptors have allosteric binding sites in addition to the γ-aminobutyric acid binding site, which respond to benzodiazepines and are located at the γ-subunit. Binding sites for neurosteroids and barbiturates are located at the β-subunit.
Function and Tasks
GABA receptors are either ligand-gated or metabotropic. Ligand-gated receptors include the GABAA and GABAC receptors. Metabotropic is only the GABAB receptor. The ligand-gated GABAA receptor is a chloride ion channel. When it binds to GABA, Cl- influxes. This influx shows inhibitory effects on the neuron. In the brain, these sub-variants are widely distributed and are responsible for the balance between excitation and attenuation in neurons. Central nervous depressant drugs such as benzodiazepines, propofol, or antiepileptic drugs bind to these receptors. The ligand-gated GABAA-ρ receptor cannot be inhibited by bicuculline. Thus, agents such as antiepileptic drugs show little effect at these sites. The metabotropic GABAB receptor is found either presynaptically or postsynaptically. When GABA binds to presynaptic receptors, there is an increased influx of K+-. The influx of Ca2+ decreases. This results in hyperpolarization: transmitter release is thus inhibited. Upon binding to the postsynaptic variant, an increased K+ influx is activated. In this way, the inhibitory postsynaptic potential is created.This type of GABA receptor is susceptible to substances such as the muscle relaxant baclofen. GABAA receptors are collectively distributed in the brain and spinal cord, where they are sometimes the most important receptors for inhibition of the central nervous system. In the basal ganglia and cerebellum, these receptors are involved in motor control. In the thalamus, the receptors help initiate and maintain sleep. In the spinal cord, GABA receptors are located on motor neurons, where they are involved in reflex circuitry and coordination of movements.
Diseases
GABA receptors are clinically and pharmacologically relevant primarily in the context of substances that can bind to them. This is true, for example, of alcohol. Alcoholic substances bind to the GABAA receptors and increase permeability to chloride ions at the nerve cell membrane. This results in hyperpolarization and the action potential frequency decreases. Because the excitatory system is simultaneously inhibited due to the binding of alcohol to NMDA receptors, alcohol has a sedative effect on humans. This relationship may be relevant in alcohol intoxication and is also an important relationship in clinical practice on chronic alcohol addicts. Apart from this, the state of the central nervous system can be influenced by pharmacological substances capable of binding to the GABA receptors. This plays an important role in clinical practice in the treatment of various, neurological diseases. The treatment of epilepsy, for example, builds on this connection, but also in general, the targeted influence of the nervous system through the administration of drugs is a main component of therapy. Tranquilizers such as benzodiazepines have a sedative effect. The same applies to barbiturates, which are often used to induce anesthesia. Antiepileptic drugs such as valproate prevent epileptic seizures by inhibiting receptors. Tiagabine inhibits reuptake of GABA and increases its concentration in the synaptic cleft, reducing epileptic seizures. Many drugs also have a stimulatory effect on GABAA receptors and thus can induce addictions. Addiction is mediated via α1-containing receptors. Their stimulation causes functional changes in specific AMPA receptors of the respective neuron in neuroplastic processes.
Typical and common diseases of the central nervous system.
- Epilepsy
- Alzheimer’s disease, dementia, Parkinson’s disease
- Depression
