Pharmacology of the GABA-A receptor

DMYTRO BEREZHNOV; MARIA CLARA GRAVIELLE; DAVID FARB,

The Handbook of Contemporary Neuropharmacology

J. Wiley and Sons, Inc

Lugar: New York; Año: 2007; p. 1 - 107

Although the human central nervous system (CNS) is undoubtedly a marvel of implementation of cellular systems, composed of roughly 1013 neurons each making thousands of synaptic connections, their functional output can be expressed in terms of a balance between excitatory and inhibitory synaptic activity. Approximately one third of brain synapses use g-aminobutyric acid (GABA) as the inhibitory neurotransmitter [1?3]. Experiments carried out during the 1950s and 1960s suggested that GABA has an inhibitory effect in the invertebrate [4?6] and the vertebrate CNS [7?15]. The molecular diversity of type A GABA (GABAA) receptor subunit genes probably evolved by a process of duplication and translocation of an ancestral gene, leading to modern-day gene clusters distributed on different human chromosomes [16?18]. L-Glutamic acid decarboxylase (GAD) catalyzes the conversion of L-glutamate to GABA via a decarboxylation resulting in the accumulation and storage of GABA within inhibitory neurons [5, 19, 20]. Upon arrival of an action potential at the nerve terminal, the presynaptic membrane depolarizes inducing the opening of voltage gated Ca2+ channels. Influx of Ca2+ ions through these channels increases its intracellular concentration and triggers the fusion of synaptic vesicles containing GABA with the presynaptic membrane. When released into the synaptic cleft GABA freely diffuses within the 20-nm synaptic cleft and binds to both post- and presynaptic receptors. Termination of synaptic transmission is achieved by clearing the neurotransmitter by a combination of diffusion out of the cleft and active transport into contiguous neuronal and/or glial cells [21]. Once recaptured by the neuron, GABA can be further transported into synaptic vesicles by vesicular GABA transporters (VGATs) or degraded by the enzyme GABA aminotransferase to succinic semialdehyde [22]. Different plasma membrane transporters are responsible for high-affinity uptake of GABA into neuronal cells. These membrane-bound transport proteins are dependent on the Naþ transmembrane gradient and may require either Cl
or K for activity [23?25]. The accumulation of intraneuronal GABA into storage vesicles theoretically increases the potential concentration gradient across the plasma membrane by compartmentalization of releasable GABA, protecting it from leakage and/or intraneuronal metabolism.