GABA Receptors Differentially Modulate Longevity In C. Elegans

Recent work has uncovered an increasingly important role of the nervous system in organismal aging.The nervous system can modulate aging via neurotransmission by secreting various singling molecules such as small neurotransmitters and neuropeptides.The worm nervous system senses cool and warm environmental temperatures through cool-and warm-sensitive neurons and then signals the gut to extend and shorten life span,respectively.It has been reported that the temperature mediated longevity modulation is not a passive chemical reaction slow-down process,but is a complex regulatory network consisting of the membrane receptors related to temperature perception and various downstream signal factors.Intestinal TRPA-1,as a cold-sensitive TRP channel,detects temperature drop in the environment to extend lifespan in C.elegans.This effect requires cold-induced,TRPA-1-mediated calcium influx and a calcium-sensitive PKC that signals to the transcription factor DAF-16/FOXO.We hypothesize TRPA-1/DAF-16 pathway most likely is not the only pathway regulating the effect of temperature on lifespan,and there would be other membrane receptors and related pathways regulating the modulation effect of temperature on lifespan.Therefore,we performed a whole-genome RNAi screen to identify genes involved in temperature modulation of lifespan in C.elegans,and 79potential candidates were picked out.We found that aex-2,the G protein-coupled receptor on the GABAergic neurons,can regulate aging in a temperature-dependent manner.Is found that NLP-40 from the intestine activate its receptor AEX-2/GPCR,stimulate stimulate the release of GABA,which in turn binds to the excitatory GABA receptor,EXP-1,and thus leads to the enteric muscle contractions(Exp).However,the regulatory mechanism of EXP-1,as an ionic GABA_A receptor,on the lifespan of C.elegans is not clear.At the same time,we have recently made the surprising observation that metabotropic GABA signaling regulates longevity in C.elegans.But,the role of other types of GABA receptors in aging and longevity modulation has not been clearly defined.It is also unclear whether GABA signaling regulates healthspan in C.elegans.So we systematically explored the regulation mechanisms of different GABA receptors on longevity in C.elegans.Here,using C.elegans as a model,we systematically interrogated the roles of various GABA receptors in both lifespan and healthspan modulation.We found that mutations in four different GABA receptors(gbb-1,unc-49,exp-1,lgc-36)extend healthspan by promoting resistance to stress and pathogen infection,and that two such receptor mutantations(gbb-1,exp-1)also promote lifespan-extension.We found that different GABA receptors engage distinct transcriptional factors to regulate lifespan and healthspan,and even the same receptor regulates lifespan and healthspan via different transcription factors.Our results uncover a novel,profound role of GABA signaling in aging and longevity regulation in C.elegans,which is mediated by different GABA receptors coupled to distinct downstream effectors.Our studies not only elucidate that distinct GABA receptors differentially modulate lifespan and healthspan in C.elegans,but also would encourage further studies to investigate how the nervous system regulates aging and longevity through diverse neurotransmitter signalling,which is an interesting but poorly understood question in the biology of aging.