Kokabu Shoichiro, Lowery Jonathan W, Toyono Takashi, Seta Yuji, Hitomi Suzuro, Sato Tsuyoshi, Enoki Yuichiro, Okubo Masahiko, Fukushima Yosuke, Yoda Tetsuya
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan; Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
Department of Biomedical Science, Marian University College of Osteopathic Medicine, 3200 Cold Spring Rd, Indianapolis, IN, 46222, USA.
Biochem Biophys Res Commun. 2015 Dec 25;468(4):568-73. doi: 10.1016/j.bbrc.2015.10.142. Epub 2015 Nov 3.
T1R3 is a T1R class of G protein-coupled receptors, composing subunit of the umami taste receptor when complexed with T1R1. T1R3 was originally discovered in gustatory tissue but is now known to be expressed in a wide variety of tissues and cell types such the intestine, pancreatic β-cells, skeletal muscle, and heart. In addition to taste recognition, the T1R1/T1R3 complex functions as an amino acid sensor and has been proposed to be a control mechanism for the secretion of hormones, such as cholecystokinin, insulin, and duodenal HCO3(-) and activates the mammalian rapamycin complex 1 (MTORC1) to inhibit autophagy. T1R3 knockout mice have increased rate of autophagy in the heart, skeletal muscle and liver. Thus, T1R3 has multiple physiological functions and is widely expressed in vivo. However, the exact mechanisms regulating T1R3 expression are largely unknown. Here, we used comparative genomics and functional analyses to characterize the genomic region upstream of the annotated transcriptional start of human T1R3. This revealed that the T1R3 promoter in human and mouse resides in an evolutionary conserved region (ECR). We also identified a repressive element located upstream of the human T1R3 promoter that has relatively high degree of conservation with rhesus macaque. Additionally, the muscle regulatory factors MyoD and Myogenin regulate T1R3 expression and T1R3 expression increases with skeletal muscle differentiation of murine myoblast C2C12 cells. Taken together, our study raises the possibility that MyoD and Myogenin might control skeletal muscle metabolism and homeostasis through the regulation of T1R3 promoter activity.
T1R3是G蛋白偶联受体T1R家族的一员，与T1R1复合时构成鲜味味觉受体的亚基。T1R3最初在味觉组织中被发现，但现在已知它在多种组织和细胞类型中表达，如肠道、胰腺β细胞、骨骼肌和心脏。除了味觉识别外，T1R1/T1R3复合物还作为一种氨基酸传感器发挥作用，并被认为是胆囊收缩素、胰岛素和十二指肠HCO3(-)等激素分泌的控制机制，它还能激活哺乳动物雷帕霉素复合物1（MTORC1）以抑制自噬。T1R3基因敲除小鼠心脏、骨骼肌和肝脏中的自噬速率增加。因此，T1R3具有多种生理功能，并且在体内广泛表达。然而，调节T1R3表达的确切机制在很大程度上尚不清楚。在这里，我们使用比较基因组学和功能分析来表征人类T1R3注释转录起始上游的基因组区域。这表明人类和小鼠的T1R3启动子位于一个进化保守区域（ECR）。我们还在人类T1R3启动子上游鉴定出一个抑制元件，该元件与恒河猴具有较高的保守度。此外，肌肉调节因子MyoD和肌细胞生成素调节T1R3的表达，并且随着小鼠成肌细胞C2C12细胞的骨骼肌分化，T1R3的表达增加。综上所述，我们的研究提出了MyoD和肌细胞生成素可能通过调节T1R3启动子活性来控制骨骼肌代谢和稳态的可能性。
