We examined the role of the ether a go-go (eag) gene in modulation of K+ currents and the possibility of its protein product Eag as a subunit in the heteromultimeric assembly of K+ channels by voltage-clamp analysis of larval muscle membrane currents. Previous DNA sequence studies indicate that the eag gene codes for a polypeptide homologous to, but distinct from, the Shaker (Sh) K+ channel subunits (Warmke et al., 1991), and electrophysiological recordings revealed allele- specific effects of eag on four identified K+ currents in Drosophila larval muscles (Zhong and Wu, 1991). Further studies of eag alleles indicated that none of the eag mutations, including alleles producing truncated mRNA messages, eliminate any of the four K+ currents, and that the mutational effects exhibit strong temperature dependence. We found that both W7, an antagonist of Ca2+/calmodulin, and cGMP analogs modulated K+ currents and that their actions were altered or even abolished by eag mutations. These results suggest a role of eag in modulation of K+ currents that may subserve integration of signals at a converging site of the two independent modulatory pathways. The Sh locus is known to encode certain subunits of the IA channel in larval muscle. The existence of multiple eag and Sh alleles enabled an independent test of the idea of Eag as a K+ channel subunit by studying IA in different double-mutant combinations. An array of allele-specific interaction between eag and Sh was observed, which reflects a close association between the Sh and eag subunits within the IA channel. Taken together, our data strengthen the possibility that the eag locus provides a subunit common to different K+ channels. The role of the eag subunit for modulating channels, as opposed to that of Sh subunits required for gating, selectivity, and conductance of the channel, suggest a combinatorial genetic framework for generating diversified K+ channels.