Articles written in Journal of Biosciences
Volume 41 Issue 4 December 2016 pp 689-695 ARTICLE
Lifespan extension is an all systems encompassing event. Involvement of reduced insulin/IGF1 signalling is wellworked out, first in the model organism Caenorhbaditis elegans followed by other systems including humans. But therole of neuronal component in lifespan extension is not well understood due to the refractory nature of neurons tosmall RNA interference (sRNAi) in C. elegans. Earlier, we have demonstrated that an antihypertensive drug,reserpine, extends lifespan through modulation of neurotransmitter release, especially, acetylcholine, in C. elegans.Intriguingly, the reserpine mediated lifespan extension (RMLE) does not happen through the known longevitypathways. Here, we report that the D2-type dopamine receptor (DOP-3), which acts through the inhibitory Gproteincoupled (Gαi) pathway mediated signalling is partly required for RMLE. In the dop-3 loss of function mutantRMLE is shortened. DOP-3 acts through Gαo (goa-1). One of the downstream targets of G protein signalling is thetranscription factor, jun-1. MRP-1, an ATP binding cassette transporter, belonging to the multidrug resistance proteinfamily is one of the genes turned on by JUN-1. RMLE is shortened in dop-3→goa-1→jun1→mrp-1 loss of functionmutants, elucidating the contribution of dop-3 signalling. The dop-3 receptor system is known to inhibit acetylcholinerelease. This suggests dopamine receptor, dop-3 could be contributing to the modulation of acetylcholine release byreserpine. ERI-1 is a 3′-5′ exoribonuclease, one of the negative regulators of sRNAi, whose loss of function makesneurons amenable to siRNA. In the absence of eri-1, RMLE is shortened. In the dop-3 loss-of-function background,lack of eri-1 completely abolishes RMLE. This suggests that dop-3 and eri-1 act in independent parallel pathways forRMLE and these two pathways are essential and sufficient for the longevity enhancement by reserpine in C. elegans.
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