SummaryIn previous work it was shown thatparats(paralyzed, temperature-sensitive,I-53.9) andnapts(no action potential, temperature-sensitive, 2-56.2), two temperature-sensitive paralytic mutations that block nerve conduction at restrictive temperatures, interact synergistically in double mutants causing unconditional lethality. This interaction is now shown to includetip-E(temperature-induced paralysis, 3-13.5), another temperature-sensitive paralytic mutation. There is an allele-dependent interaction betweentip-Eand variousparaalleles resulting in the unconditional lethality of the most extreme double mutant combinations. The pattern of this allele-dependency is strikingly different from that previously reported fornaptsandparain that theparaalleles that interact strongest withnaptsinteract weakest withtip-Eand vice-versa. Double mutants oftip-Ewithnaptsalso display greatly reduced viability. Surviving double mutants oftip-Ewith eitherparats1ornaptsare weak and exhibit enhanced temperature sensitivity for both paralysis and nerve conduction failure. In addition, in atip-Ebackground, mutantparaalleles enhance temperature-sensitive paralysis even when heterozygous withpara+. The results of these studies suggest thattip-Eshares related function withparaandnapIt is proposed thattip-E, likeparaandnapexerts an effect at some level on the structure, function, or stability of sodium channels.