An activating mutation in a Caenorhabditis elegans G(s) protein induces neural degeneration

Abstract

Heterotrimeric guanine nucleotide-binding proteins (G proteins) act as signal-transducing molecules that connect serpentine-transmembrane receptors to a variety of intracellular effectors. We characterized a Caenorhabditis elegans G(s) gene, gsa-1, which encodes a G(s) α-subunit (Gα(s)) that is expressed throughout the nervous system and in muscle cells. gsa-1 is an essential gene; a loss-of-function mutation in gsa-1 results in lethality at the first stage of larval development. Partial (mosaic) loss of Gα(s) expression or overexpression of the protein results in reciprocal defects in movement and egg-laying, suggesting a role for Gα(s) in the regulation of these behaviors. Expression of a constitutively active form of Gα(s) from an inducible promotor results in hypercontraction of body-wall muscle cells and vacuolization and degeneration of neurons within hours of induction. Neurons that are susceptible to the degeneration induced by activated Gα(s) are predominantly motoneurons located within the ventral nerve cord. Phenotypic analysis shows that the induced neural degeneration is not the result of programmed cell death but is probably caused by the activation of ion channels. A genetic suppressor of activated Gα(s) was isolated that identifies a putative downstream target of G(s) signaling.