Intracellular Peptide Signaling in Neurobiology

Intracellular peptide signalling represents an emerging paradigm in neurobiology, in which short peptide fragments generated by proteasomal degradation or specific endopeptidases act as bioactive messengers within neurons. These peptides, often 5–20 amino acids in length, can modulate receptor function, protein–protein interactions and intracellular trafficking pathways. Rather than serving solely as intermediates on the way to complete proteolysis, many of these fragments bind directly to signalling proteins—such as G protein-coupled receptors, kinase complexes and RNA-binding proteins—thereby influencing synaptic plasticity, neuronal survival and the stress response. Enzymes including thimet oligopeptidase and neurolysin control the pool of intracellular peptides, shaping both the temporal and spatial dynamics of peptide-mediated signals. Dysregulation of intracellular peptide levels has been linked to neurodegenerative disease, altered pain perception and mood disorders, highlighting the global significance and therapeutic potential of targeting peptide generation and turnover in the central nervous system.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Intracellular Peptide Signaling in Neurobiology publication trend

The graph below shows the total number of articles in intracellular peptide signaling in neurobiology across all publications each year (not limited to Nature Index journals).

Technical terms

Intracellular peptides: Short fragments generated by protein degradation that act as signalling ligands within the cell.

Ubiquitin–proteasome system: A multi-enzyme pathway that tags proteins with ubiquitin and degrades them into peptides.

Thimet oligopeptidase (THOP1): A zinc-dependent endopeptidase that processes many intracellular peptides and regulates their signalling functions.

Neurolysin: A metallopeptidase involved in the catabolism of neuropeptides and in the regulation of intracellular peptide levels.

G protein-coupled receptor (GPCR): A membrane receptor family that transduces extracellular signals into intracellular responses, targetable by intracellular peptides.

References

1. Intracellular Peptides as Natural Regulators of Cell Signaling*. Journal of Biological Chemistry (2008).
2. Thimet Oligopeptidase (EC 3.4.24.15) Key Functions Suggested by Knockout Mice Phenotype Characterization. Biomolecules (2019).
3. A Novel Intracellular Peptide Derived from G1/S Cyclin D2 Induces Cell Death*. Journal of Biological Chemistry (2014).