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GABAergic Synapse Pathway

A maintained balance between excitatory and inhibitory synaptic transmission plays a crucial role in normal function and long-term homeostasis of the neuronal circuits. While glutamatergic synaptic transmission acts as the primary mode of excitatory neurotransmission mediating fast neuronal communication in central nervous system (CNS), inhibitory synapses are thought to provide a brake to neural firing and are important for a number of purposes which include, but are not limited to, preventing postsynaptic neurons from reaching threshold, modulating the pattern of action potential firing, and modifying synaptic strength. Inhibitory strength is not constant but must adapt to dynamically changing patterns and degrees of network activity.

GABA Synthesis, Uptake and Release

Gamma-Aminobutyric acid (γ-Aminobutyric acid, GABA) is the predominating inhibitory neurotransmitter in the mammalian CNS. As exogenous GABA cannot penetrate the blood-brain barrier, it is synthesized in the GABAergic neurons in the CNS, converted from glutamate, the principal excitatory neurotransmitter, using the enzyme glutamic acid decarboxylase (GAD) and pyridoxal phosphate as a cofactor. GAD appears to be expressed only in cells that use GABA as a neurotransmitter. Once synthesized, GABA is packaged into vesicles by vesicle GABA transporters (VGAT), releases to the synaptic cleft when the presynaptic neuron is depolarized, and diffuses across the cleft to the target receptors distributed on the postsynaptic surface.

In addition, GABA released into the synapse cleft can be reuptaken into both presynaptic terminals and surrounding glial cells for different purposes. Relying on membrane GABA transporters (GAT), GABA taken back up into presynaptic terminals is available for reutilization, while GABA in glial cells is metabolized to succinic semialdehyde by GABA-T and cannot be resynthesized in this compartment since glia lack GAD. Ultimately, GABA can be recovered from this source by a circuitous route involving the Krebs cycle. GABA in glia is converted to glutamine by a metabolic pathway called the GABA shunt; and glutamine is transferred back to the presynaptic neurons, where glutamine is converted to glutamate by enzyme glutaminase.

GABA shunt reactions are responsible for the synthesis, conservation and metabolism of GABA.

Figure 1. GABA shunt reactions are responsible for the synthesis, conservation and metabolism of GABA. (Raven et al., 1999.)

GABAA Receptor

Mostly localized to postsynaptic sites in the CNS, GABAA receptors are GABA-gated chloride channels that belong to the Cys-loop ligand-gated ion channel superfamily. Upon GABA binding, these ionotropic receptors that are permeable to Cl-, hereby creating a short increase in the anion conductance, which leads to the hyperpolarization of a depolarized membrane. These short events have been termed phasic inhibition, while GABAA receptors localized to extrasynaptic sites cause the so-called tonic inhibition. Assembled in the endoplasmic reticulum, GABAA receptors are heteromeric pentamers formed by 5 subunits from 7 subunit subfamilies (α, β, γ, δ, ε, θ and π), and most of them are composed of two α, two β, and one γ (or δ) subunits. Following assembly, transport-competent GABAA receptors are trafficked to the Golgi apparatus and segregated into vesicles for transport to, and insertion into, the plasma membrane, which is facilitated by a number of receptor-associated proteins including GABA receptor-associated protein (GABARAP) and N-ethylmaleimide-sensitive factor (NSF). In addition, neuronal GABAA receptors undergo extensive endocytosis, recycling or degradation under the regulation of an endocytic trafficking factor huntingtin-associated protein (HAP) 1. GABAA receptors on the postsynaptic membrane contains recognition sites for multiple compounds: (a) GABA in two GABA binding sites at the interface between α and β subunits; (b) benzodiazepine binding site at the interface between α and γ2 subunits; and (c) barbiturates, ethanol, and neurosteroids bind to sites in the membrane-spanning transmembrane regions of the subunits.

Schematic illustration of the GABAA receptor

Figure 2. Schematic illustration of the GABAA receptor. (Jacbo et al., 2010)

GABAB Receptor

In addition to fast actions via GABAA receptors, GABA also modulates neural activity on a slower time scale through the activation of GABAB receptors, which are metabotropic receptors belonging to G protein-coupled receptors superfamily. GABAB receptors are obligatory heterodimers composed of by 2 subunits, GABAB1 that contains a large extracellular binding domain that binds GABA or other ligands, and GABAB2 that couples the receptor with the effector G protein. Therefore, GABAB1 and GABAB2 subunits must be co-expressed to form a functional GABAB receptor. GABAB receptor predominantly couples to Gi/o proteins, which dissociated into Gα and Gβγ dimer when GABAB receptor is activated by GABA. The Gαi/o subunit can inhibit adenylyl cyclase (AC) and the Gβγ dimer is capable to modulate voltage-gated Ca2+ channels (VGCC) or G protein-gated inwardly rectifying K+ (GIRK) channels, both leading to potent neuronal inhibition. GABAB receptors are situated on postsynaptic axons as well as presynaptic terminals where they inhibit excess neurotransmitter release.

Structure of GABAB receptors subunit composition

Figure 3. Structure of GABAB receptors subunit composition. (Benarroch, 2012)

GABAC Receptor

The second type of ionotropic GABA receptor, GABAC (also known as GABAA-rho) receptor is a subclass of GABAA receptors composed entirely of rho (ρ) subunits. GABAC receptors have a higher sensitivity for GABA but smaller currents than GABAA receptors. They are characterized by longer mean open times and smaller chloride conductance. GABAC receptors are distributed in many regions in the CNS with as especially high expression in the retina, which therefore provides a unique function in retinal signal processing.

A schematic representation of GABAC receptors subunit composition

Figure 4. A schematic representation of GABAC receptors subunit composition.

References:

1. Siegel GJ, Agranoff BW, Albers RW, et al., Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
2. Jacob T C, Moss S J, Jurd R. GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nature Reviews Neuroscience, 2008, 9(5): 331-343.
3. Sigel E, Steinmann M E. Structure, function, and modulation of GABAA receptors. Journal of Biological Chemistry, 2012, 287(48): 40224-40231.
4. Benarroch E E. GABAB receptors Structure, functions, and clinical implications. Neurology, 2012, 78(8): 578-584.
5. Padgett C L, Slesinger P A. GABA B receptor coupling to G-proteins and ion channels. Advances in pharmacology, 2010, 58: 123-147.
6. Enz R. GABAC receptors: a molecular view. Biological chemistry, 2001, 382(8): 1111-1122.

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