Finally, we discuss neuropeptide signaling systems that act upstream of GABAARs and exert their neural

effects in part through altered GABAAR trafficking. GABAARs are members of the superfamily of heteropentameric ligand-gated ion channels that also include the nicotinic acetylcholine receptors, glycine receptors, and 5-HT3 receptors (Figure 1A) (reviewed in Unwin, 1989 and Barnard et al., 1998). The subunits of all these receptors share a common ancestral structure that includes an extracellular N-terminal domain, four transmembrane domains (TM1-4), and an extended cytoplasmic loop region between TM3 Selleckchem Compound C and TM4 that mediates interactions with trafficking and signaling factors (Figures 1B and 1C). GABAAR subunits are encoded by 19 different genes that have been grouped into eight subclasses based on sequence homology (α1-6, β1-3, γ1-3, δ, ɛ, θ, π, ρ1-3). Alternative splicing contributes to additional receptor

Talazoparib in vitro diversity. In particular, the γ2 (Whiting et al., 1990) and β2 subunits (McKinley et al., 1995) exist as short and long splice variants distinguished by the presence or absence of eight and 38 amino acids, respectively. Different subunit combinations give rise to a large number of structurally and functionally distinct GABAAR subtypes. Based on a recent conservative count, 11 structurally and functionally distinct receptor subtypes have been conclusively identified and are reasonably abundant in at least parts PDK4 of the brain. They represent combinations of 2α and 2β subunits together with a single γ2 or δ subunit. An additional 15 receptor subtypes exist with high probability and a more limited distribution (Olsen and Sieghart, 2008).

These numbers do not account for additional heterogeneity based on two different types of α or β subunits in one receptor complex (Khan et al., 1996 and Benke et al., 2004), or due to alternative splicing of subunits. GABAARs with different subunit compositions exhibit different pharmacology and channel gating properties, are differentially expressed during development and in the adult brain, accumulate at different neuronal cell surfaces, and are subject to differential regulation by extracellular cues. The subsets of GABAARs at synapses are composed of two α1, α2, or α3 subunits together with two β2 or β3 subunits and a single γ2 subunit. Compared to other GABAAR subtypes discussed below, these receptors exhibit low affinity for GABA and thus are optimized to respond selectively to relatively high concentrations of GABA released into the synaptic cleft (300 μM, Perrais and Ropert, 1999). The γ2 subunit is essential for postsynaptic clustering of GABAARs (Essrich et al., 1998). However, the γ3 subunit can substitute for the γ2 subunit and contribute to postsynaptic GABAARs in the developing postnatal brain (Baer et al., 1999).