This review focuses on GABAA receptors (GABAARs) that are excluded from synapses (see Figure 1). It has long been appreciated that ligand-gated

ion channels Vorinostat manufacturer that bind glutamate and GABA are found outside synapses in the somatic, dendritic, and even axonal membranes of mammalian neurons (Brown et al., 1979 and Soltesz et al., 1990). The first indication that a persistent, tonic conductance could result from activation of extrasynaptic GABAAR populations came from whole-cell voltage-clamp recordings made from developing neurons when synapses are being formed (Ben-Ari et al., 1994, Kaneda et al., 1995 and Valeyev et al., 1993). In these experiments, the addition of GABAAR blockers reduced the standing holding current indicating that a tonic GABAAR-mediated conductance had to be present that was not associated with conventional IPSCs (Otis et al., 1991). It is believed that

these early developmental forms of GABA signaling may play a role in controlling neuronal differentiation (LoTurco et al., 1995, Markwardt et al., 2011 and Owens et al., 1999). This type of intercellular communication is fundamentally different from the “point-to-point” communication that underlies both synaptic transmission and gap-junction-mediated electrical coupling. It is more similar to the volume and paracrine transmission associated with the actions of neuromodulators such as serotonin, histamine, dopamine, acetycholine, and peptides in the brain (Agnati et al., 2010). Attention has subsequently focused on the molecular identity GABA cancer of the extrasynaptic GABAARs

that generate the tonic conductance and on exploring their physiological relevance for the adult brain (Farrant and Nusser, 2005). GABAARs are pentameric assemblies usually made up from at least three different proteins selected Cediranib (AZD2171) from 19 different subunits (Olsen and Sieghart, 2008). These include α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3 (Olsen and Sieghart, 2008, Olsen and Sieghart, 2009 and Whiting, 2003). A receptor’s regional and developmental expression pattern, as well as its physiological and pharmacological properties, are determined by differences in subunit gene expression and composition (Hevers and Lüddens, 1998 and Mody and Pearce, 2004) and the rules governing these relationships have received a great deal of attention in the search for highly specific drug targets in the CNS (Olsen and Sieghart, 2009 and Whiting, 2003). The subunit identity of the final assembly also determines the synaptic or extrasynaptic localization of GABAARs within a neuron (Pirker et al., 2000), reflecting the existence of various subunit assembly rules and anchoring/trafficking mechanisms (Luscher et al., 2011 and Vithlani et al., 2011). Following the original description of the GABAAR δ-subunit (Shivers et al., 1989) and its expression patterns in the brain (Wisden et al.