Recent evidence suggest that exposure to volatile anesthetic agents causes a change in conductance through an undelineated potassium channel. With recently developed genetic and molecular techniques the Drosophila melanogaster (D.m.) genome can be manipulated to study the role that potassium ion channel function plays in anesthetic action. The IA potassium channel is encoded by the Shaker (Sh) locus on the X chromosome of D.m. Because this channel may be one of those involved in volatile anesthetic action, we tested the sensitivity to isoflurane in three Shaker strains with different degrees of dysfunctional IA conductance (Shnull greater than ShKS133 greater than Sh5). Anesthetic sensitivity was also examined in mutant strains of D.m. which express abnormalities either in other potassium channel conductances (eag, slo) or other ion conductances (para). The normally conducting wild type served as the control. Two-day-old adult D.m. were stimulated with a heat source during exposure to the volatile anesthetic isoflurane, and the number moving in response to the noxious stimulus was noted. After testing the Shaker and control strains at no fewer than 13 concentrations, the IC50S (isoflurane concentration in percent vol/vol at which 50% of the flies did not respond to the heat stimulus) were derived. The IC50 values for Sh 5 (0.89), Sh133 (1.29), and Shnull (1.37) were significantly different from the wild type (0.56). The rank order of insensitivity of these Shaker mutants corresponded to the extent of the alteration in IA conductance as established by previous studies in these mutants. Neither eag (0.66), para (0.48), nor slo (0.63) differed significantly from the wild type. These data suggest that the IA potassium channel plays a role in volatile anesthetic action.