Adenylyl cyclases convert intracellular ATP into cyclic AMP, a major second messenger molecule in the cell. Mammalian membrane-bound adenylyl cyclases consist of a short cytoplasmic N-terminal sequence, a six-transmembrane spanning region and a cytoplasmic catalytic domain, followed by a second six-transmembrane spanning region and a second cytoplasmic catalytic domain. In C. elegans , at least four genes show significant sequence similarity to mammalian adenylyl cyclases:
sgs-1 ,
acy-2 ,
acy-3 and
acy-4 .
sgs-1 was previously reported to encode an adenylyl cyclase that shows a general neuronal expression pattern (Korswagen et al. , 1998). We have isolated a null allele of
sgs-1 , and animals homozygous for this allele show retarded development and arrest in variable larval stages. Furthermore, these animals exhibit lethargic movement and pharyngeal pumping, and, while sterile, have a life span that is nearly twice as long as that of Bristol N2 animals. We isolated an extensive set of reduction-of-function mutations in
sgs-1 in a screen for suppressors of a neuronal degeneration phenotype induced by expression of a constitutively activated version of the heterotrimeric G-alpha-s subunit of C. elegans . These reduction-of-function mutants do not have altered lifespan or pharyngeal pumping compared to Bristol N2 animals, but preliminary results suggest that they have reduced locomotion rates. The reduction-of-function alleles show differences in their degree of suppression of the neuronal degeneration, in their locomotion rate and in their growth in trans to the null allele. Based on that, we have placed the reduction-of-function alleles in an allelic series.
acy-2 was previously reported to have a more restricted expression pattern than
sgs-1 , and loss of
acy-2 results in early larval lethality (Korswagen et al. , 1998). Probably, ACY-2 performs an essential function in the CAN cells together with G-alpha-s.
acy-3 and
acy-4 are most similar to mammalian adenylyl cyclase type V.
acy-3 is expressed in support cells of ciliated neurons in head and tail ganglia and in 2 pairs of neurons in the retrovesicular ganglia. In addition, it is highly expressed in the spermatheca. We are currently studying the expression pattern of
acy-4 , and we are screening a chemical deletion library to isolate
acy-3 and
acy-4 null alleles. References: H.C. Korswagen, A.M. van der Linden, and R.H.A. Plasterk. (1998) G protein hyperactivation of the Caenorhabditis elegans adenylyl cyclase SGS-1 induces neuronal degeneration. Embo J. 17, 5059-5065