The cAMP concentration in Drosophila is increased by mutations of the dunce (dnc) gene and decreased by mutations of the rutabaga (rut) gene. Such mutants provide a unique means for exploring the role of cAMP in functional and developmental regulation of membrane currents. Four distinct K+ currents have been identified in Drosophila larval muscle fibers, i.e. the voltage-activated transient IA and delayed IK and the Ca(2+)-activated fast ICF and slow ICS. Results from our voltage-clamp studies indicated that both IA and IK were increased in dnc alleles. Normal muscle fibers treated with dibutyryl-cAMP showed a similar increase of IA, but no significant effect on IK. In contrast to the dnc alleles, the rut mutations appeared to enhance ICS greatly while leaving the amplitude of other currents largely unchanged. In addition, the dibutyryl-cAMP-induced increase in IA was not observed in rut fibers. Caffeine and W7, which are known to interfere with several second messenger pathways, also modulated K+ currents in larval muscle fibers. The currents in dnc and rut fibers showed strikingly altered responses to caffeine and W7. The results demonstrate that the various K+ currents in Drosophila muscles are affected by altered cAMP cascades in the mutants. The fact that not all dnc and rut mutant defects can be mimicked or reversed by acute application of cAMP suggests that long-term modulation of K+ currents by cAMP may involve mechanisms distinct from the short-term effect of cAMP.