Sedation and Anesthesia Mediated by Distinct GABA_AReceptor Isoforms

Abstract

The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA(A) receptors, with selectivity for beta2 and beta3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive beta2 subunit (beta2 N265S) to determine the role of beta2 and beta3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through beta3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the beta2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes.

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…The hypnotic effects of phenobarbital and the GABA A receptor β2/3 specific agonist etomidate (Reynolds et al, 2003) was assessed in wild-type and Fmr1 knockout mice, in light of our findings of GABAergic protein dysregulation in the forebrain (Figures 5-8). Mice were examined for the duration of sleep after i.p.…”

Sleep and general anesthesia

“…In the case of the point mutant, the reduced sensitivity has been mapped to at least the perifornical area (Pef) and the tuberomammillary nucleus neurons (G, redrawn), 77 but the extent of their involvement and other possible targets within and outside of the sleep circuitry have yet to be determined Sleep and general anesthesia 145 recorded in the LC were still able to be prolonged by the anesthetic. 77 It would be interesting to see whether this test would support anesthetic actions in arousal pathways when applied to other knock-in (e.g., b 2 N265S) 82 or knockout (e.g., two pore domain acid-sensitive potassium channel-3) 65 mice. Another exciting resolution to this problem may be the advance of cell-targeted genetic technologies, particularly those using viral delivery systems.…”

Low dose acute alcohol effects on GABAA receptor subtypes

“…Fully consistent with this notion is our finding that tonic currents in cerebellar granule cells are highly sensitive to EtOH and therefore must contain the β3 subunit, and that the β3 subunit-containing receptors mediate the in vivo anesthetic effects of etomidate and propofol because a point mutation in the β3 subunit (N265M) that eliminates etomidate and propofol effects on recombinant receptors in knock-in mice essentially eliminates etomidate and propofol anesthetic effects (Jurd et al, 2003). In contrast, a similar mutation in the β2 subunit (β2N265S) only eliminates the sedative "side" effects of etomidate and propofol but not the anesthetic effects (Reynolds et al, 2003). Therefore it is tempting to speculate that the β3 selectivity of these GABA-anesthetic drugs could be due to the fact that in many brain regions δ subunit-containing receptors are associated with the β3 subunit (although there are exceptions, e.g., the thalamus expresses only low amounts of the β3 subunit and the abundant δ likely is paired with α4β2; Sieghart & Sperk, 2002).…”