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

突触之间神经传递的完整性是由于几种跨突触粘附蛋白。然而，只有teneurins，latrophilins（LPHN）和纤连蛋白富含亮氨酸的跨膜蛋白是无脊椎动物和脊椎动物之间的保守。端神经元是与脊椎动物感觉通路形成相关的粘附蛋白。所有4种脊椎动物端神经元在其胞外结构域的末端区域都具有生物活性肽样序列，称为端神经元C-末端相关肽（TCAP）。TCAP-1独立地转录为来自teneurin-1的短mRNA。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蛋白转运到质膜中来增加葡萄糖摄取到脑中，并伴随刺激轴突和树突发育。此外，在体内，TCAP-1增加了大脑边缘区的棘密度形成。所述端神经元和LPHN形成跨突触对，其中LPHN受体蛋白在突触前表达，而端神经元配体在突触后表达。LPHN与辅助蛋白肌营养不良蛋白聚糖（dystroglycan）相关。teneurin和TCAP-1都与LPHN结合，并与肌营养不良蛋白聚糖密切相关。TCAP-1刺激细胞内磷酸化级联反应以调节与肌营养不良蛋白聚糖作用一致的细胞骨架结构，但抑制LPHN诱导的与teneurin结合相关的活化。我们假设，游离TCAP-1作为竞争性激动剂，teneurin-LPHN配体-受体对作为一种负反馈机制，以正常化的稳态的情况下，慢性感觉刺激。因为在脊椎动物中有4个teneurin和3个LPHN，但在被囊动物基因组中只有单拷贝的teneurin、LPHN、CRF及其受体，我们将使用被囊动物和啮齿动物模型来检查TCAP-1的作用，以确定TCAP-1在LPHN结合方面的不同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压力相关的稳态的基本调节，还有助于对兽医，水产养殖和医学相关领域中与压力相关的病理学提供新的理解。

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.