Epilepsy and movement disorders in the GABAA receptor β3 subunit knockout mouse: model of Angelman syndrome

GABA A receptor structure and function: multiple subunit genes, and implications for epilepsy and movement disorders? γ-Aminobutyric acid type A (GABA A ) receptors (GABAR) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system (Olsen & DeLorey, 1999). The GABAR belong to the superfamily of ligand-gated ion channel receptors, i.e. they are ion channel proteins whose opening is controlled by the binding of the neurotransmitter (DeLorey & Olsen, 1992). These GABAR are a family of heteropentamers formed from a family of at least 19 related subunits in mammals, named α(1–6), β(1–4), γ(1–3), δ, ε, π, and ρ(1–3) (Tyndale et al., 1995; Davies et al., 1997; Hedblom & Kirkness, 1997). Splicing variants exist for some subunits, primarily related to phosphorylation substrates in the intracellular loop, e.g. the γ2 subunit longer version (γ2L) contains an 8 amino acid insert in the cytoplasmic loop that contains a consensus substrate site for phosphorylation by protein kinase C that is missing in γ2S (Burt & Kamatchi, 1991; McKernan & Whiting, 1996). Important CNS drug targets are present on GABAR, notably sites for the benzodiazepines, barbiturates, neurosteroids, other general anesthetics, and picrotoxin-like convulsants (Macdonald & Olsen, 1994). The individual subunits show variable regional and temporal expression. A dozen or more heteropentameric isoforms of the GABAR occur naturally with reasonable abundance; these exhibit various pharmacological properties and presumably biological properties as well (Lüddens et al., 1995; McKernan & Whiting, 1996; Barnard et al., 1998).