Genetic reduction of GABAA receptor γ2 subunit expression potentiates the immobilizing action of isoflurane

Potentiation of inhibitory γ-aminobutyric acid subtype A (GABAA) receptor function is involved in the mechanisms of anesthetic action. The present study examined the immobilizing action of the volatile anesthetic isoflurane in mice with double knockout (DKO) of phospholipase C-related inactive protein (PRIP)-1 and -2. Both of these proteins play important roles in the expression of GABAA receptors containing the γ2 subunit on the neuronal cell surface. Immunohistochemistry for GABAA receptor subunits demonstrated reduced expression of γ2 subunits in the spinal cord of the DKO mice. Immunohistochemistry also revealed up-regulation of the α1 and β3 subunits even though there were no apparent differences in the immunoreactivities for the β2 subunits between wild-type and DKO mice. The tail-clamp method was used to evaluate the anesthetic/immobilizing effect of isoflurane and the minimum alveolar concentration (MAC) was significantly lower in DKO mice compared with wild-type controls (1.07 ± 0.01% versus 1.36 ± 0.04% atm), indicating an increased sensitivity to isoflurane in DKO mice. These immunohistochemical and pharmacological findings suggest that reduced expression of the GABAA receptor γ2 subunit affects the composition and function of spinal GABAA receptors and potentiates the immobilizing action of isoflurane.