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

突触间神经传递的完整性是由于几种跨突触粘附蛋白。然而，在无脊椎动物和脊椎动物之间，只有腱神经蛋白、嗜乳蛋白（LPHN）和纤维连接蛋白富含亮氨酸的跨膜蛋白是保守的。腱蛋白是与脊椎动物感觉通路形成相关的粘附蛋白。所有4种脊椎动物的腱鞘蛋白在其胞外区域的末端区域都具有生物活性的肽样序列，称为腱鞘蛋白c末端相关肽（TCAP）。TCAP-1作为tenneurin -1的短mRNA独立转录。TCAP-1在啮齿动物和被囊动物中具有许多神经和行为作用，特别是表明促肾上腺皮质激素释放因子（CRF）相关应激反应的减少和葡萄糖摄取能力的增加。在体内，TCAP-1通过增加葡萄糖转运体向质膜的易位而增加葡萄糖进入大脑的摄取，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的脊柱密度形成。腱鞘蛋白和LPHN形成一个跨突触对，其中LPHN受体蛋白在突触前表达，而腱鞘蛋白配体在突触后表达。lphn与一种辅助蛋白——糖醛酸失调蛋白相关。tenneurin和TCAP-1都与LPHN结合，并与糖醛酸异常密切相关。TCAP-1刺激细胞内磷酸化级联调节与糖醛酸异常作用一致的细胞骨架结构，但抑制lphn诱导的与腱鞘蛋白结合相关的激活。我们假设游离的TCAP-1在慢性感觉刺激情况下作为竞争性激动剂对神经神经元- lphn配体-受体对的负反馈机制，使体内平衡正常化。由于脊椎动物中有4个腱神经蛋白和3个LPHN，但在被囊动物基因组中只有腱神经蛋白、LPHN、CRF及其受体的单拷贝，因此我们将使用被囊动物和啮齿动物模型来研究TCAP-1的作用，以确定TCAP-1在LPHN结合方面的独特功能，以及葡萄糖代谢在与CRF相关的应激的稳态调节方面的相关作用。这些发现将有助于理解多细胞生物中与压力相关的稳态的基本调控，并有助于对兽医、水产养殖和医学相关领域的压力相关病理提供新的理解。

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.