Insensitivity to anaesthetic agents conferred by a class of GABAA receptor subunit

Abstract

A common feature of general anaesthetic agents is their ability to potentiate neuronal inhibition through GABA(A) (gamma-aminobutyric acid) receptors. At concentrations relevant to clinical anaesthesia, these agents cause a dramatic stimulation of the chloride currents that are evoked by the binding of the natural ligand, GABA. Although there is widespread evidence that the sensitivity of GABA(A) receptors to anaesthetic agents is heterogeneous, the structural basis of these differences is largely unknown. Variations in subunit composition can have profound effects on the sensitivity of GABA(A) receptors to modulatory agents such as benzodiazepines. However, strict subunit specificity has not been demonstrated for the potentiating effects of anaesthetic agents. Here we describe a new class of human GABA(A) receptor subunit (epsilon) that can assemble with alpha- and beta-subunits and confer an insensitivity to the potentiating effects of intravenous anaesthetic agents. The epsilon-subunit also abolishes the normal outward rectification of recombinant receptors in which it assembles. The expression pattern of this subunit in the brain suggests a new target for manipulation of neuronal pathways within the basal ganglia.

A Novel Class of GABAA Receptor Subunit in Tissues of the Reproductive System

“…3 Notably, no hybridizing transcripts were detected in samples of whole brain or pancreas. It appears that the subunit is expressed in only a minor subpopulation of cells in these tissues.…”

“…In mammals, the 14 known subtypes of GABA A receptor subunits have been categorized within five structural classes (␣1-6, ␤1-3, ␥1-3, ␦, ⑀). These subunits are thought to assemble in different pentameric complexes, with most functional receptors containing ␣/␤/(␥, ␦, or ⑀) subunit combinations (1)(2)(3). A sixth class of subunit ( ) form homomeric GABA receptors that do not appear to coexist with GABA A receptor subunits and correspond pharmacologically to a related (GABA C ) receptor subtype (4,5).…”

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

“…The ε subunit shares the greatest sequence homology with the γ subunits, and so it is generally thought to take the place of the single γ subunit in the pentameric receptor. However studies examining the sensitivity of recombinant ε-containing receptors to the positive neurosteroids have provided varying results in which the extent of enhancement by the positive neurosteroids of current through recombinant GABA A receptors appears to be inversely proportional to the level of ε subunit expression (Davies et al, 1997;Whiting et al, 1997;Thompson et al, 1998). A recent study by Thompson et al (2002) suggest that the discordant findings with respect to steroid sensitivity of these ε-containing receptors can be reconciled if it is assumed that ε can substitute for not only for the γ, but also for non-γ subunits within the pentamer such that receptors with alternative stoichiometries are produced as ε subunit expression increases.…”

Identification of Residues within GABAAReceptor α Subunits That Mediate Specific Assembly with Receptor β Subunits

“…GABA A receptors are members of the ligand-gated ion channel superfamily that includes glycine, nicotinic acetylcholine (AChR), and 5-HT 3 receptors (Unwin, 1993). Molecular cloning has revealed a range of GABA A receptor subunits that can be divided by homology into subunit classes with multiple members: ␣(1-6), ␤ (1-3), ␥(1-3), ␦, ⑀, and (MacDonald and Olsen, 1994;Rabow et al, 1995;Davies et al, 1997;Hedblom and Kirkness, 1997). There is considerable spatial and temporal variation in subunit expression, with many neuron types expressing multiple numbers of receptor subunits (Laurie et al, 1992;MacDonald and Olsen, 1994;Rabow et al, 1995).…”