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: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630459
• 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取决于几种突触粘附蛋白。然而，在无脊椎动物和脊椎动物之间仅保守蛋白、肌松蛋白 (LPHN) 和富含亮氨酸的纤连蛋白跨膜蛋白。 Teneurins 是与脊椎动物感觉通路形成相关的粘附蛋白。所有 4 种脊椎动物的 teneurin 在其胞外结构域的末端区域都具有生物活性肽样序列，称为 teneurin C 端相关肽 (TCAP)。 TCAP-1 独立转录为 tenurin-1 的短 mRNA。 TCAP-1 在啮齿类动物和被囊类动物中具有多种神经和行为作用，特别表明与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蛋白易位到质膜中来增加大脑对葡萄糖的摄取，并同时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棘密度的形成。 teneurin 和 LPHN 形成跨突触对，其中 LPHN 受体蛋白在突触前表达，而 teneurin 配体在突触后表达。 LPHN 与辅助蛋白肌营养不良聚糖相关。 teneurins 和 TCAP-1 均与 LPHN 结合，并与肌营养不良聚糖密切相关。 TCAP-1 刺激细胞内磷酸化级联反应，调节与肌营养不良聚糖作用一致的细胞骨架结构，同时抑制 LPHN 诱导的与 teneurin 结合相关的激活。我们假设游离 TCAP-1 作为 teneurin-LPHN 配体-受体对的竞争性激动剂，作为负反馈机制，在慢性感觉刺激的情况下使体内平衡正常化。由于脊椎动物中有 4 个 teneurin 和 3 个 LPHN，但被囊动物基因组中只有单拷贝的 teneurin、LPHN、CRF 及其受体，因此我们将使用被囊动物和啮齿动物模型检查 TCAP-1 的作用，以确定 TCAP-1 在 LPHN 结合方面的独特功能以及葡萄糖代谢在 CRF 相关应激的稳态调节方面的相关作用。这些发现将有助于了解多细胞生物中与应激相关的稳态的基本调节，同时有助于为兽医、水产养殖和医学相关领域的应激相关病理学提供新的理解。