Characterization of Endoproteolytic Processing of Tachykinins and Substance P using Mouse Spinal Cord Cellular Fractions and High-Resolution Mass Spectrometry

摘要

We provide evidence that proteolysis controls SP levels in the spinal cord and Tach58-71 is effectively the precursor of SP. Both peptides were degraded rapidly when exposed to mouse spinal cord S9 fractions and had a relatively short half-lives. The metabolic stability of the C-terminal fragments allowed these metabolites to access to NK1 receptors and play a fundamental role in nociception. Thus fragments SP3-11 and SP5-11 could be important pain biomarkers. Additionally, we clearly demonstrated that PREP is involved in the N-terminal processing of Tach58-71 and SP leading to the formation of SP3-11 and SP5-11. The metabolic turnover of SP and its C-terminal metabolites is central to the neurochemistry of pain and details studies may unveil innovative treatment strategy by favoring the production of inactive peptide fragments. However, it is important to understand inter dependence of the pronociceptive and the endogenous opioid system. The significant reduction of pronociceptive peptide concentrations may impaired the endogenous opioid system response.