4-Thio-UTP is a UTP analog and potent P2Y2 and P2Y4 agonist with EC50 values of 35 and 350nM for hP2Y2 and hP2Y4, respectively[1]. P2Y2 and P2Y4 are G-protein-coupled purinergic receptors activated extracellularly by UTP that mobilize intracellular Ca²⁺ and thereby regulate epithelial ion/water transport, immune cell recruitment and vascular tone[2]. 4-Thio-UTP is widely used to investigate purinergic signaling in inflammation, epithelial ion transport, neurotransmission, and immune regulation[3]. 4-Thio-UTP is also used in cross-linking experiments and for labeling transcription complexes to explore the behavior of RNA polymerase during transcription elongation and termination[4].
In vitro, 4-Thio-UTP (0.1-300μM; 20min) evoked a concentration-dependent accumulation of [³H]inositol polyphosphates in cultured rat aortic smooth muscle cells[5].
In vivo, 4-Thio-UTP (100μM; 15min; basolateral perfusion) stimulated chloride secretion in wild-type mouse jejunum and the response was attenuated in both P2Y4-and P2Y2-deficient mice[6]. 4-Thio-UTP (0.44mg/kg; i.v.; 30min before LAD ligation) reduced myocardial infarct size and improved left-ventricular fractional shortening in wild-type mice but lost protection in P2Y2⁻/⁻mice[7].
References:
[1] Jacobson KA, Costanzi S, Ivanov AA, et al. Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5'-triphosphate analogues at the human P2Y2 and P2Y4 receptors. Biochem Pharmacol. 2006;71(4):540-549.
[2] Hede SE, Amstrup J, Klaerke DA, Novak I. P2Y2 and P2Y4 receptors regulate pancreatic Ca(2+)-activated K+ channels differently. Pflugers Arch. 2005;450(6):429-436.
[3] Lazarowski ER, Boucher RC. UTP as an extracellular signaling molecule. News Physiol Sci. 2001;16:1-5.
[4] Bartholomew B, Dahmus ME, Meares CF. RNA contacts subunits IIo and IIc in HeLa RNA polymerase II transcription complexes. J Biol Chem. 1986;261(30):14226-14231.
[5] Kumari R, Goh G, Ng LL, Boarder MR. ATP and UTP responses of cultured rat aortic smooth muscle cells revisited: dominance of P2Y2 receptors. Br J Pharmacol. 2003;140(7):1169-1176.
[6] Ghanem E, Robaye B, Leal T, et al. The role of epithelial P2Y2 and P2Y4 receptors in the regulation of intestinal chloride secretion. Br J Pharmacol. 2005;146(3):364-369.
[7] Cohen R, Shainberg A, Hochhauser E, et al. UTP reduces infarct size and improves mice heart function after myocardial infarct via P2Y2 receptor. Biochem Pharmacol. 2011;82(9):1126-1133.
4-Thio-UTP是UTP的类似物，也是强效P2Y2和P2Y4受体激动剂，对hP2Y2和hP2Y4 的EC50分别为35nM和350nM[1]。P2Y2与P2Y4是经UTP激活的G蛋白偶联嘌呤能受体，可动员细胞内Ca²⁺，进而调节上皮离子/水的转运、免疫细胞募集及血管张力[2]。4-Thio-UTP被广泛用于研究炎症、上皮离子转运、神经传递和免疫调节中的嘌呤能信号[3]。4-Thio-UTP也用于交联实验和标记转录复合体，以探索RNA聚合酶在转录延伸与终止过程中的行为[4]。
体外研究表明，4-Thio-UTP（0.1-300μM；20min）可在培养的大鼠主动脉平滑肌细胞中浓度依赖性地诱导[³H]肌醇多磷酸积聚[5]。
体内实验中，4-Thio-UTP（100μM；15min；基底侧灌流）可刺激野生型小鼠空肠的氯离子分泌，且在P2Y4或P2Y2缺失小鼠中该反应减弱[6]。4-Thio-UTP（0.44mg/kg；结扎前30min静脉注射）可缩小心肌梗死面积并改善野生型小鼠左室短轴缩短率，而在P2Y2⁻/⁻小鼠中失去保护作用[7]。