INSENSITIVITY TO ANESTHETIC AGENTS CONFERRED BY A CLASS OF GABA(A) RECEPTOR SUBUNIT

A common feature of general anaesthetic agents is their ability to pot entiate neuronal inhibition through GABA(A) (gamma-aminobutyric acid) receptors(1). At concentrations relevant to clinical anaesthesia, thes e agents cause a dramatic stimulation of the chloride currents that ar e evoked by the binding of the natural ligand, GABA. Although there is widespread evidence that the sensitivity of GABA(A) receptors to anae sthetic agents is heterogeneous(2-4), the structural basis of these di fferences is largely unknown. Variations in subunit composition can ha ve profound effects on the sensitivity of GABA(A), receptors to modula tory agents such as benzodiazepines(5). However, strict subunit specif icity has not been demonstrated for the potentiating effects of anaest hetic agents(6-10). Here we describe a new class of human GABA(A) rece ptor subunit (epsilon) that can assemble with alpha- and beta-subunits and confer an insensitivity to the potentiating effects of intravenou s anaesthetic agents. The epsilon-subunit also abolishes the normal ou tward rectification of recombinant receptors in which it assembles. Th e expression pattern of this subunit in the brain suggests a new targe t for manipulation of neuronal pathways within the basal ganglia.