GABA-receptors

GABA, gamma-aminobutyric acid, an amine of butyric acid, is a non-proteinogenic amino acid (the position of the amino group on the gamma carbon atom with respect to the carboxy group distinguishes it from the proteinogenic alpha-amino acids), with the molecular formula C4H9NO2. GABA is found in almost all prokaryotic and eukaryotic organisms. GABA is the major inhibitory neurotransmitter in the CNS (Graefe KH et al. 2016). Approximately 17-20% of all neurons in the brain are GABAergic. GABA receptors play a significant role during the development of neuronal structures in the brain. Here, initially in the fetus, GABA often has an excitatory effect on newly formed neuronal connections, contributing to their establishment.

The inhibitory effect of GABA is mediated by 2 types of receptors (see figure) (Chebib et al. 1999).

• Metabotropic receptors: These are coupled to signaling proteins and to G-proteins (guanosine triphosphate-sensitive proteins); they are more abundant than ionotropic receptors. The effects of metabotropic receptors are slower, longer lasting, more diffuse, more variable than those of ionotropic receptors. The receptor protein winds its way in and out of the cell seven times through the cell membrane. The receptor is coupled to a section of signaling protein outside the cell (e.g., outside a neuron). Inside the cell, the receptor protein is coupled to a G protein. When the neurotransmitter GABA binds to a metatropic receptor, a subunit of the G protein splits off. Depending on the G protein, this binds to a nearby ion channel. In the case of a neurotransmitter ligand, an "inhibitory postsynaptic potential" (IPSP) or an "excitatory postsynaptic potential" (EPSP) is triggered, or the synthesis of a secondary messenger ("second messenger"), which diffuses through the cytoplasm and can influence the activity of the neuron. The GABAB -receptor, is a metabotropic receptor that occurs in 2 isoforms that appear to function only together as a dimeric receptor protein.
• Ionotropic receptors: Ionotropic receptors are coupled to ligand-gated (=transmitter-gated) ion channels. Activation of an ionotropic receptor by binding its ligand (e.g. GABA) leads to an immediate opening of the ion channel. This immediately induces a PSP (postsynaptic potential). The GABAA receptor is such an ionotropic receptor, whose ion channel mediates a Cl- current after activation by GABA (see figure).

Structure and function of GABA receptors:

GABAA receptors consist of pentameric proteins. Several families and subunits have been identified (alpha, beta, gamma, delta) which also occur in different isoforms. However, most GABAa receptors consist of 2 alpha subunits, two beta subunits and a gamma2 subunit.

Activation of GABAA receptors results in the release of GABA from presynapses and induces a chloride current (through) along a concentration gradient from the synaptic cleft into the postsynaptic cell. This chloride influx hyperpolarizes the postsynaptic membrane. This results in an increase in the resting membrane potential from -65 mV to -70 mV. This results in an inhibitory postsynaptic potential (IPSP).

The GABAA-ρ recept or (originally called the GABAC receptor) is also an ionotropic receptor. It differs from the GABAA receptor in that it is composed of ρ-subunits. Pharmacological agents such as benzodiazepines and barbiturates are ineffective at this receptor.

Function of GABA receptors (Inhibitory neurotransmission by GABA): The most important function of GABAergic receptors is to trigger rapid, synaptic (phasic) neurotransmission. Furthermore, GABAA receptor types are also involved in tonic inhibition caused by continuous activation of extrasynaptic GABAA receptors (Semyanov et al., 2004). However, the distinction between phasic and tonic inhibition is blurred; it has been found that phasic, 'slow' inhibition can occur through transmitter spillover at 'perisynaptic' and 4 extrasynaptic receptors. This phenomenon is produced by transmitter 'spillover' (Wei et al., 2003).

GABA-mediated phasic transmission is produced at high concentrations of GABA (0.3-1.0 mM) (Gaiarsa et al., 2002). This amount of GABA remains in the synaptic cleft for a very short time (<1 ms). Released GABA can interact with postsynaptic GABAA receptors. Coupling of GABA with the receptors places them in the active state, resulting in an inhibitory postsynaptic current (IPSC) (Chen et al., 2000). Perisynaptic GABAA receptors are subsequently activated by "transmitter spillover" (Wei et al., 2003). As a result, phasic GABA release activates not only synaptic GABAA receptors.

Many cells are activated by tonic currents. These are produced by micromolar concentrations of GABA. Such low concentrations of GABA are found in the extracellular space at all times (Tossman et al.1986). The charge that occurs during tonic activation of the receptors is three times stronger than during phasic inhibition, although the frequency of phasic events is much greater (Semyanov et al.2003).

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