Sugimoto Akira, Oka Kaori, Sato Rui, Adachi Shinji, Baker Michael E, Katsu Yoshinao
Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
Faculty of Fisheries Sciences, Hokkaido University, Hakodate, Japan.
Biochem J. 2016 Oct 15;473(20):3655-3665. doi: 10.1042/BCJ20160579. Epub 2016 Aug 12.
The response to a panel of steroids by the mineralocorticoid receptor (MR) from Amur sturgeon and tropical gar, two basal ray-finned fish, expressed in HEK293 cells was investigated. Half-maximal responses (EC50s) for transcriptional activation of sturgeon MR by 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol and aldosterone, and progesterone (Prog) were between 13 and 150 pM. For gar MR, EC50s were between 8 and 55 pM. Such low EC50s support physiological regulation by these steroids of the MR in sturgeon and gar. Companion studies with human and zebrafish MRs found higher EC50s compared with EC50s for sturgeon and gar MRs, with EC50s for zebrafish MR closer to gar and sturgeon MRs than was human MR. For zebrafish MR, EC50s were between 75 and 740 pM; for human MR, EC50s were between 65 pM and 2 nM. In addition to Prog, spironolactone (spiron) and 19nor-progesterone (19norP) were agonists for all three fish MRs, in contrast with their antagonist activity for human MR, which is hypothesized to involve serine-810 in human MR because all three steroids are agonists for a mutant human Ser810Leu-MR. Paradoxically, sturgeon, gar, and zebrafish MRs contain a serine corresponding to serine-810 in human MR. Our data suggest alternative mechanism(s) for Prog, spiron, and 19norP as MR agonists in these three ray-finned fishes and the need for caution in applying data for Prog signaling in zebrafish to human physiology.
研究了在HEK293细胞中表达的两种基干辐鳍鱼——黑龙江鲟和热带雀鳝的盐皮质激素受体（MR）对一组类固醇的反应。11-脱氧皮质酮、皮质酮、11-脱氧皮质醇、皮质醇、醛固酮和孕酮（Prog）对鲟鱼MR转录激活的半数最大反应（EC50）在13至150 pM之间。对于雀鳝MR，EC50在8至55 pM之间。如此低的EC50支持这些类固醇对鲟鱼和雀鳝中MR的生理调节。与人类和斑马鱼MR的对照研究发现，与鲟鱼和雀鳝MR的EC50相比，其EC50更高，斑马鱼MR的EC50比人类MR更接近雀鳝和鲟鱼MR。对于斑马鱼MR，EC50在75至740 pM之间；对于人类MR，EC50在65 pM至2 nM之间。除了Prog，螺内酯（spiron）和19-去甲孕酮（19norP）对所有三种鱼类MR都是激动剂，这与它们对人类MR的拮抗活性形成对比，据推测这涉及人类MR中的丝氨酸810，因为所有三种类固醇对突变型人类Ser810Leu-MR都是激动剂。矛盾的是，鲟鱼、雀鳝和斑马鱼MR含有与人类MR中丝氨酸810相对应的丝氨酸。我们的数据表明，Prog、spiron和19norP作为这三种辐鳍鱼中MR激动剂的替代机制，以及在将斑马鱼中Prog信号的数据应用于人类生理学时需要谨慎。
