Page - (000189) - in Biomedical Chemistry: Current Trends and Developments

2005). Inhibitory neurotransmission in the adult nervous system is primarily mediated by the exocytosis of synaptic vesicles containing GABA and glycine. GABAergic inhibition predominates in the brain, whereas both glycine and GABA act as the primary inhibitory neurotransmitter in the spinal cord and brainstem. To date, a single vesicular transporter was identified for the filling of synaptic vesicles at both GABAergic and glycinergic synapses; it is referred to as vesicular GABA transporter (VGAT) (McIntire, 1997) or vesicular inhibitory amino acid transporter (VIAAT) (Sagne, 1997). GABA exerts its effects through three types of receptors, named GABAA, GABAB and GABAC receptors. The different GABA receptor subtypes were originally characterized based on their pharmacological properties. GABAA receptors are ionotropic chloride channels, the activation of GABAA receptors allows the influx of chloride, hyperpolarizing the membrane and decreasing the excitability of the cell. The chloride homeostasis in neurons is determined by two major transporters, the Na+-K+-Cl- co-transporter, NKCC1 (a Cl- accumulator), and the K+-Cl- co-transporter KCC2 (a Cl- exporter) (Ben-Ari, 2002; Owens, 2002). During embryonic development and maturation, neurons downregulate NKCC1 expression and upregulate KCC2 expression, resulting in a lower [Cl-]i in most mature neurons. The fast inhibitory actions of GABA are mediated by the activation of GABAA receptors in the brain. A similar role is played by GABAC receptors in the retina. GABAB receptors are metabotropic receptors that address second messenger systems through the binding and activation of guanine nucleotide-binding proteins (G proteins) (Campbell, 1993). GABAB receptors predominantly couple to Giα- and Goα-type G proteins (Pinard, 2010). It is now well established that presynaptic GABAB receptors repress Ca2+ influx by inhibiting Ca2+ channels in a membrane-delimited manner via the Gβγ subunits. Postsynaptic GABAB receptors trigger the opening of K+ channels, again through the Gβγ subunits (Bettler, 2006). This results in a hyperpolarization of the postsynaptic neuron (Luscher, 1997). Besides modulating ion channels through Gβγ, GABAB receptors activate and inhibit adenylyl cyclase via the Giα/Goα and Gβγ subunits. Presynaptic GABAB receptors are subdivided into those that control GABA release (autoreceptors) and those that inhibit all other neurotransmitter release