Neurotrophins are initially synthesized as larger precursors (proneurotrophins), which undergo proteolytic cleavage to yield mature forms. Although the functions of the mature neurotrophins have been well established during neural development and in the adult nervous system, roles for the proneurotrophins in developmental and injury-induced cell death, as well as in synaptic plasticity, have only recently been appreciated. Interestingly, both mature neurotrophins and proneurotrophins utilize dual-receptor complexes to mediate their actions. The mature neurotrophin coreceptors consist of the Trk receptor tyrosine kinases and p75 NTR , wherein Trk transduces survival and differentiative signaling, and p75 NTR modulates the affinity and selectivity of Trk activation.On the other hand, proneurotrophins engage p75 NTR and the structurally distinct coreceptor sortilin, to initiate p75 NTR -dependent signal transduction cascade. Although the specificity of mature neurotrophins vs. proneurotrophins actions is due in part to the formation of distinct coreceptor complexes, a number of recent studies highlight how different p75 NTR -mediated cellular actions are modulated. Here, we review emerging evidence for a novel transmembrane mechanism for ligand-specific p75 NTR activation and several mechanisms by which p75 NTR -dependent apoptotic and nonapoptotic responses can be selective activated. ' 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 350-359, 2010

Many extracellular signals are transmitted to the interior of the cell by receptors with seven membrane-spanning helices that trigger their effects by means of heterotrimeric guanine-nucleotide-binding regulatory proteins (G proteins). These G-protein-coupled receptors (GPCRs) control various physiological functions in evolution from pheromone-induced mating in yeast to cognition in humans. The potential role of the G-protein signalling system in the control of animal ageing has been highlighted by the genetic revelation that mutation of a GPCR encoded by methuselah extends the lifespan of adult Drosophila flies. How methuselah functions in controlling ageing is not clear. A first essential step towards the understanding of methuselah function is to determine the ligands of Methuselah. Here we report the identification and characterization of two endogenous peptide ligands of Methuselah, designated Stunted A and B. Flies with mutations in the gene encoding these ligands show an increase in lifespan and resistance to oxidative stress. We conclude that the Stunted-Methuselah system is involved in the control of animal ageing.