Seven transmembrane receptors and their associated heterotrimeric guanine nucleotide-binding proteins (G proteins) have been proposed to play a key role in modulating the activities of neurons and muscles. The physiological function of the Caenorhabditis elegans G protein G(o) has been genetically characterized. Mutations in the goa-l gene, which encodes an a subunit of G(o) (G alpha(o)), cause behavioral defects similar to those observed in mutants that lack the neurotransmitter serotonin (5-HT), and goa-1 mutants are partially resistant to exogenous 5-HT. Mutant animals that lack G alpha(o) and transgenic animals that overexpress G alpha(o) [goa-l(xs) animals] have reciprocal defects in locomotion, feeding, and egg laying behaviors. In normal animals, all of these behaviors are regulated by 5-HT. These results demonstrate that the level of G(o) activity is a critical determinant of several C. elegans behaviors and suggest that G(o) mediates many of the behavioral effects of 5-HT.