Ancient interaction between the teneurin C-terminal associated peptides (TCAP) and latrophilin ligand-receptor coupling: a role in behavior

Abstract

Teneurins are multifunctional transmembrane proteins that are found in all multicellular animals and exist as four paralogous forms in vertebrates. They are highly expressed in the central nervous system, where they exert their effects, in part, by high-affinity binding to latrophilin (LPHN), a G-protein coupled receptor (GPCR) related to the adhesion and secretin GPCR families. The teneurin C-terminal associated peptides (TCAPs) are encoded by the terminal exon of all four teneurins, where TCAPs 1 and 3 are independently transcribed as soluble peptides, and TCAPs 2 and 4 remain tethered to their teneurin proprotein. Synthetic TCAP-1 interacts with LPHN, with an association with β-dystroglycan, to induce a tissue-dependent signal cascade to modulate cytoskeletal dynamics. TCAP-1 reduces stress-induced behaviors associated with anxiety, addiction and depression in a variety of models, in part, by regulating synaptic plasticity. Therefore, the TCAP-1-teneurin-LPHN interaction represents a novel receptor-ligand model and may represent a key mechanism underlying the association of behavior and neurological conditions.

Keywords: adhesion GPCR; molecular evolution; neuroendocrine interactions; stress; synapse.

Figure 1

Schematic of teneurin-TCAP protein structure. The intracellular amino terminus contains polyproline (pp) sites and EF-hand-like Ca²⁺ binding motifs (EF). The extracellular domain is composed of eight epidermal growth factor (EGF)-like repeats, a cysteine-rich region, followed by 26 tyrosine-aspartic acid (YD) repeats. Finally, the carboxy terminus contains the TCAP structure with 40–41 residues. Drawing is not to scale.

Figure 2

Schematic interpretation of the teneurin/TCAP-latrophilin complex in the trans-synaptic region. Current evidence suggests that teneurins interact with both the lectin-like (LEC) and olfactomedin-like (OLF) binding domains. We further postulate that TCAP interacts with the hormone-binding domain (HBD) of latrophilin, and associates with β-dystroglycan to activate the MEK-ERK1/2 pathway leading to cytoskeletal reorganization and synaptic plasticity (Adapted from Chand et al., 2012b). Teneurin/TCAP and latrophilins, together with α–dystroglycan, neurexin and fibronectin leucine-rich transmembrane protein (FLRT) play a role with the stabilization of the trans-synaptic region.