Stress and nutrient uptake in chordates: Defining a novel highly conserved receptor-ligand system

脊索动物的压力和营养吸收：定义一种新型的高度保守的受体-配体系统

• 批准号: RGPIN-2015-06331
• 负责人: Lovejoy, David
• 金额: $ 2.4万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=685041
• 关键词: Stress; nutrient; uptake; chordates; Defining

The integrity of neural transmission between synapses is due to several transynaptic adhesion proteins. However, only the teneurins, latrophilins (LPHN) and fibronectin leucine-rich transmembrane proteins are conserved between invertebrates and vertebrates. The teneurins are adhesion proteins associated with the formation of sensory pathways in vertebrates. All 4 vertebrate teneurins possess a bioactive peptide-like sequence in the terminal region of their extracellular domain termed the teneurin C-terminal associated peptide (TCAP). TCAP-1 is independently transcribed as a short mRNA from teneurin-1. TCAP-1 has a number of neurological and behavioural actions in rodents and tunicates indicating, in particular, a decrease in the corticotropin-releasing factor (CRF)-associated stress-response, and an increase in glucose-uptake abilities. In vivo, TCAP-1 increases glucose uptake into the brain by increasing glucose transporter translocation into the plasma membrane and concomitantly stimulates axon and dendritic development. Moreover, in vivo, TCAP-1 increases spine density formation in limbic regions of the brain. The teneurins and LPHNs form a transynaptic pair where LPHN receptor proteins are expressed presynaptically, and the teneurin ligands, postsynaptically. The LPHNs are associated an accessory protein, dystroglycan. Both teneurins and TCAP-1 bind to LPHN and associate closely with the dystroglycans. TCAP-1 stimulates an intracellular phosphorylation cascade to regulate cytoskeleton structure consistent with dystroglycan actions, yet inhibits the LPHN-induced activation associated with teneurin binding. We hypothesize that free TCAP-1 acts as competitive agonist to teneurin-LPHN ligand-receptor pair as a negative feedback mechanism to normalize homeostasis in situation of chronic sensory stimulation. Because there 4 teneurins and 3 LPHNs in vertebrates, but only single copies of teneurin, LPHN, CRF and its receptor in the tunicate genome, we will examine the effects of TCAP-1 using both tunicate and rodent models to determine the distinct function of TCAP-1 with respect to LPHN-binding and the associated role of glucose metabolism with respect to the homeostatic regulation of CRF-associated stress. These findings will help understand the fundamental regulation of stress-associated homeostasis in multicellular organisms, yet help provide a novel understanding of stress-related pathologies in veterinary, aquaculture and medicine-related fields.

突触之间神经传递的完整性是由于几种跨突触黏附蛋白的作用。然而，在无脊椎动物和脊椎动物之间，只有Teneurins、Latrophins(LPHN)和富含纤维连接蛋白亮氨酸的跨膜蛋白是保守的。Teneurin是一种黏附蛋白，与脊椎动物感觉通路的形成有关。所有4种脊椎动物的Teneurin在其胞外区的末端都有一个类似生物活性的多肽序列，称为TCAP。TCAP-1是由Teneurin-1独立转录而来的短mRNA。TCAP-1在啮齿动物和被毛类动物中具有许多神经和行为作用，尤其表明促肾上腺皮质激素释放因子(CRF)相关的应激反应减少，葡萄糖摄取能力增加。在体内，TCAP-1通过增加葡萄糖转运体到质膜的转运量来增加大脑对葡萄糖的摄取，并伴随着刺激轴突和树突的发育。此外，在体内，TCAP-1增加了大脑边缘区域的脊椎密度形成。Teneurin和LPHN形成跨突触对，其中LPHN受体蛋白在突触前表达，Teneurin配体在突触后表达。LPHN与一种辅助蛋白--营养不良糖链有关。Teneurins和TCAP-1都与LPHN结合，并与营养不良糖链紧密结合。TCAP-1刺激细胞内的磷酸化级联反应来调节细胞骨架结构，与肌营养不良蛋白的作用一致，但抑制LPHN诱导的与Teneurin结合相关的激活。我们假设，在慢性感觉刺激的情况下，游离TCAP-1作为Teneurin-LPHN配体-受体对的竞争性激动剂，作为一种负反馈机制来正常化动态平衡。由于脊椎动物中有4个Teneurin和3个LPHN，但在被囊基因组中只有Teneurin、LPHN、CRF及其受体的单拷贝，因此我们将使用被膜和啮齿动物模型来研究TCAP-1的作用，以确定TCAP-1在LPHN结合方面的不同功能以及糖代谢在CRF相关应激的动态平衡调节中的相关作用。这些发现将有助于理解多细胞生物体中应激相关稳态的基本调节，同时也有助于对兽医、水产养殖和医学相关领域中应激相关病理的新理解。