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

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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.