Effects Of Caenorhabditis Elegans GABA_B Receptor On The Regulation Of Oxidative Stress

With the development of human society, more and more people care about health and longevity. So people pay more and more attention to the mechanism of ageing. Many published data indicate that from poikilotherms to homeothermic animals, the ageing can be co-regulted by environmental and genetic factors, like lifespan of C. elegans is 14 days at 25 degree celsius, but more 30 days at 15 degree celsius; and down- regulation of the body temperature of rat 0.5 degree celsius can extend the lifespan significantly. At the same time, there are some genes mutant can extend or shorten lifespan at the same condition, for example mutations that decrease the level of daf-2, which is the mammal insulin/IGF-1 receptor ortholog gene, cause the animal to live more than twice as long.Recently, our data(unpublished) showed that the mutation that lower the level of gbb-1(such as gbb-1(tm1406)), which encodes an mammal GABAB receptor homologue, can extend life span of the nematode, and unc-25, a synthesis enzyme for gaba, have the same phenotype as the gene gbb-1. As we all know, those gene regulting ageing almost participated in modulating the resistance to harsh condition. So we speculated gbb-1(tm1406) mutant may enhance the resistance to adversity. Then we tested several conditions and we found gbb-1(tm1406) mutant can improve the survival rate under 35 degree celsius and treated with paraquat or TPHP depending on FOXO family transcription factor DAF-16. More interestingly, the ortholog gene of PKD,dkf-2 and the ortholog gene of PLC?, egl-8, can also regulate the resistance to oxidative stress.Taken together, the research showed us GABAB receptor in C. elegans can regulate the resistance to oxidative stress depending on DAF-16, and the signal from GABAB receptor to DAF-16 is conducted by dkf-2 and egl-8. In mammal, GABAB receptor is very important, which is a main medicine target and related to many diseases, especially neurogenic diseases like depression, epilepsy, addiction, Parkinson and so on. As to the high homology of GABAB receptor in mammal and gbb-1(tm1406) mutant in C. elegans, we can use the C. elegans as a model to do a large scale screen for those drug molecules which can active or inhibite GABAB receptor, depending on the phenotype we found, that will be low cost and efficient and promising.