Neuronally expressed Ras-family GTPase Di-Ras modulates synaptic activity in Caenorhabditis elegans.
Ras-family GTPases regulate a wide variety of cellular functions including cell growth and differentiation. Di-Ras, which belongs to a distinct subfamily of Ras-family GTPases, is expressed predominantly in brain, but the role of Di-Ras in nervous systems remains totally unknown. Here, we report that the Caenorhabditis elegans Di-Ras homologue drn-1 is expressed specifically in neuronal cells and involved in synaptic function at neuromuscular junctions. Loss of function of drn-1 conferred resistance to the acetylcholinesterase inhibitor aldicarb and partially suppressed the aldicarb-hypersensitive phenotypes of heterotrimeric G-protein mutants, in which acetylcholine release is up-regulated. drn-1 mutants displayed no apparent defects in the axonal distribution of the membrane-bound second messenger diacylglycerol (DAG), which is a key stimulator of acetylcholine release. Finally, we have identified EPAC-1, a C. elegans Epac homologue, as a binding partner for DRN-1. Deletion mutants of epac-1 displayed an aldicarb-resistant phenotype as drn-1 mutants. Genetic analysis of drn-1 and epac-1 showed that they acted in the same pathway to control acetylcholine release. Furthermore, DRN-1 and EPAC-1 were co-immunoprecipitated. These findings suggest that DRN-1 may function cooperatively with EPAC-1 to modulate synaptic activity in C. elegans.
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Minoru
M
Tada
Keiko
K
Gengyo-Ando
Tetsuo
T
Kobayashi
Masamitsu
M
Fukuyama
Shohei
S
Mitani
Kenji
K
Kontani
Toshiaki
T
Katada
D000109:Acetylcholine / Q000235:genetics / Q000378:metabolism; D000448:Aldicarb / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D059329:Cholinergic Neurons / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004351:Drug Resistance; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D009469:Neuromuscular Junction / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D025941:Protein Interaction Mapping; D017384:Sequence Deletion; D009435:Synaptic Transmission
D029742:Caenorhabditis elegans Proteins; D002800:Cholinesterase Inhibitors; C516620:GOA-1 protein, C elegans; D020662:Guanine Nucleotide Exchange Factors; D000448:Aldicarb; D020558:GTP Phosphohydrolases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000109:Acetylcholine