Ascr#2

Ascr#2 is a type of ascaroside in Caenorhabditis elegans that can effectively induce the worm to enter the dauer stage (a dormant larval stage) with EC₅₀ values of approximately 370nM at 25℃ and 1100nM at 20℃^[1]. Ascr#2 exhibits a male-attracting effect on C. elegans at lower concentrations than those required for dauer induction when combined with Ascr#3^[2]. Ascr#2-mediated effects are facilitated through G protein-coupled receptors (GPCRs) including DAF-37, DAF-38, SRBC-64 and SRBC-66^[3][4].

In vitro, Ascr#2 (50, 100nM) treated HEK293 cells transfected with cMyc-DAF-37 and/or HA-DAF-38 for 30min enhanced the formation of DAF-37 homodimers as well as the heterodimers between DAF-37 and DAF-38^[3]. Ascr#2 (1, 10μM) treated HEK293 cells coexpressing SRBC-64 and SRBC-66, but not each receptor alone, for 15min significantly inhibited forskolin-mediated increases in cAMP levels, which indicated that co-expression of SRBC-64 and -66 is sufficient to confer Ascr#2-dependent responses in vitro^[4].

In vivo, Ascr#2 (100nM; 3days) promoted C. elegans development arrest and reduced developmental acceleration by nacq#1. The results confirmed the dauer-inducing effect of Ascr#2 and suggested the antagonism between nacq#1 and Ascr#2^[5]. Ascr#2 (0.04, 4, and 400nM) treatment of C. elegans for up to 25 days enhanced both lifespan and stress resistance in a concentration-dependent manner. Ascr#2 (400nM) exposure on sir-2.1(ok434) mutant C. elegans for 25 days displayed lifespan regulation mediated by the sirtuin-dependent signaling pathway^[6].

References:
[1] Butcher R.A., Fujita M., Schroeder F.C.,Jon Clardy J. Small-molecule pheromones that control dauer development in Caenorhabditis elegans.Nat Chem Biol. 2007 Jul;3(7):420-2.
[2] Choe, A.; von Reuss, S.H.; Kogan, D.; et al. Ascaroside Signaling is Widely Conserved Among Nematodes. Curr. Biol. 2012, 22, 772–780.
[3] Park D., O’Doherty I., Somvanshi R.K., et al. Interaction of structure-specific and promiscuous G-protein-coupled receptors mediates small-molecule signaling in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 2012, 109, 9917–9922.
[4] KimK.H., Sato KJ, Shibuya M, et al. Two chemoreceptors mediate developmental effects of dauer pheromone in C. elegans. Science. 2009 Nov 13;326(5955):994-8.
[5] Ludewig A.H., Artyukhin B.A., Aprison E.Z., et al. An excreted small molecule promotes C. elegans reproductive development and aging. Nat Chem Biol. 2019 Aug;15(8):838-845.
[6] Ludewig A.H., Izrayelit Y., Park D., et al. Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1.Proc Natl Acad Sci USA. 2013 Mar 18;110(14):5522–5527.

Ascr#2是秀丽隐杆线虫（Caenorhabditis elegans）中的一种蛔虫苷，能有效诱导线虫进入休眠幼虫期，25℃时EC₅₀值约为370nM，20℃时EC₅₀值约为1100nM^[1]。Ascr#2和Ascr#3在较低浓度下具有引诱雄性秀丽隐杆线虫的作用^[2]。Ascr#2介导的效应是通过G蛋白偶联受体（GPCRs）实现的，其中包括DAF-37、DAF-38、SRBC-64和SRBC-66^[3][4]。

在体外，Ascr#2（50、100nm）处理转染cMyc-DAF-37和/或HA-DAF-38的HEK293细胞30分钟后，可增强DAF-37同型二聚体的形成以及DAF-37和DAF-38之间的异源二聚体的形成^[3]。Ascr#2（1、10μM）作用于共表达SRBC-64和SRBC-66的HEK293细胞（但不是单独表达每种受体）15分钟，显著抑制forskolin介导的cAMP水平升高，这表明SRBC-64和-66的共表达足以在体外产生Ascr#2依赖性反应^[4]。

在体内，Ascr#2（100nM，3days）导致秀丽隐杆线虫的发育停滞，并降低nacq#1的加速发育作用。结果证实了Ascr#2诱导线虫进入休眠幼虫期，并提示nacq#1与Ascr#2之间存在拮抗作用^[5]。Ascr#2（0.04、4和400nM）处理线虫长达25天，以浓度依赖的方式提高了线虫的寿命和抗逆性。sir-2.1(ok434) 突变体秀丽隐杆线虫暴露于Ascr#2（400nM）25天，显示Ascr#2的寿命调节作用依赖于sirtuin信号通路介导^[6]。