Abstract
Peptides play a major role in the transmission of information to and from the central nervous system. However, because of their structural complexity, the development of pharmacological peptide-based therapeutics has been challenged by the lack of understanding of endogenous peptide evolution. The teneurin C-terminal associated peptides (TCAP) possess many of the required attributes of a practical peptide therapeutic. TCAPs, associated with the teneurin transmembrane proteins that bind to the latrophilins, members of the Adhesion family of G-protein-coupled receptors (GPCR). Together, this ligand-receptor unit plays an integral role in synaptogenesis, neurological development, and maintenance, and is present in most metazoans. TCAP has structural similarity to corticotropin-releasing factor (CRF), and related peptides, such as calcitonin and the secretin-based peptides and inhibits the (CRF)-associated stress response. Latrophilins are structurally related to the secretin family of GPCRs. TCAP is a soluble peptide that crosses the blood-brain barrier and regulates glucose transport into the brain. We posit that TCAP represents a phylogenetically older peptide system that evolved before the origin of the CRF-calcitonin-secretin clade of peptides and plays a fundamental role in the regulation of cell-to-cell energy homeostasis. Moreover, it may act as a phylogenetically older peptide system that evolved as a natural antagonist to the CRF-mediated stress response. Thus, TCAP's actions on the CNS may provide new insights into the development of peptide therapeutics for the treatment of CNS disorders.
Highlights
The central nervous system (CNS) communicates information to the peripheral tissues primarily by neurotransmitter-mediated modulation of tonic and phasic ionic conductance among cells
If we posit that homeostatic peptides regulate the synaptic plasticity of key regions of the CNS associated both with energy metabolism and reward- and fear-based learning behavior, this indicates that bioactive peptides must, regulate the energy requirements of the associated neurons
terminal associated peptides (TCAP)-based peptides are phylogenetically ancient and are critical to the homeostasis of vertebrates. Because they and their receptor evolved in a single celled progenitor of multicellular organisms, they have become evolutionarily ensconced into numerous metabolic functions, notably within the CNS
Summary
TCAPs, associated with the teneurin transmembrane proteins that bind to the latrophilins, members of the Adhesion family of G-protein-coupled receptors (GPCR). Together, this ligand-receptor unit plays an integral role in synaptogenesis, neurological development, and maintenance, and is present in most metazoans. We posit that TCAP represents a phylogenetically older peptide system that evolved before the origin of the CRF-calcitonin-secretin clade of peptides and plays a fundamental role in the regulation of cell-to-cell energy homeostasis It may act as a phylogenetically older peptide system that evolved as a natural antagonist to the CRF-mediated stress response.
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