Expression of a constitutively activated mutant of the heterotrimeric G protein alpha-subunit Galpha-s results in the swelling and vacuolization of a specific subset of ventral nerve cord motoneurons. A second site modifier (
sgs-1) that completely suppresses this neuronal degeneration was isolated.
sgs-1 was cloned and was shown to encode an adenylyl cyclase that is most similar to mammalian adenylyl cyclase type IX. Mutations in
sgs-1 change residues that are conserved among different adenylyl cyclases. These mutations are located in the two catalytic domains and in the first multiple transmembrane spanning region of the predicted protein. An
sgs-1::gfp reporter construct shows a general neuronal expression pattern, demonstrating that
sgs-1 is expressed in the neurons that are susceptible to activated Galpha-s-induced cell death. These results suggest that SGS-1 is a target of Gas signalling in neurons and that this interaction is critical for activated Galpha-s-induced neurotoxicity. The identification of
sgs-1 as an adenylyl cyclase prompted us to search the C. elegans sequence database for additional adenylyl cyclase genes. A second predicted adenylyl cyclase is encoded by C10F3.3 (
acy-2). We show that
acy-2::gfp is expressed in the canal-associated neurons (CAN) and that loss of
acy-2 results in an L1 larval lethal phenotype. The
clr-1 like appearance of
acy-2 null mutant animals suggests a defect in the CAN cells, a phenotype that is also similar to Gas null mutant animals. Therefore, we speculate that Galpha-s interacts with SGS-1 in ventral nerve cord moto-neurons, whereas Galpha-s interacts with ACY-2 in the CAN cells.