Tachykinins Processing is Significantly Impaired in PC1 and PC2 Mutant Mouse Spinal Cord S9 Fractions
Article [Accepted Manuscript]
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Neurochemical research ; vol. 40, no. 11, pp. 2304-2316.Abstract(s)
Substance P (SP) play a central role in nociceptive transmission and it is an agonist of the
Neurokinin-1 receptor located in the lamina I of the spinal cord. SP is a major proteolytic product
of the protachykinin-1 primarily synthesized in neurons. Proprotein convertases (PCs) are
extensively expressed in the central nervous system (CNS) and specifically cleave at C-terminal
of either a pair of basic amino acids, or a single basic residue. The proteolysis control of
endogenous protachykinins has a profound impact on pain perception and the role of PCs remain
unclear. The objective of this study was to decipher the role of PC1 and PC2 in the proteolysis
surrogate protachykinins (i.e. Tachykinin 20-68 and Tachykinin 58-78) using cellular fractions of
spinal cords from wild type (WT), PC1-/+ and PC2-/+ animals and mass spectrometry. Full-length
Tachykinin 20-68 and Tachykinin 58-78 was incubated for 30 minutes in WT, PC1-/+ and PC2-/+
mouse spinal cord S9 fractions and specific C-terminal peptide fragments were identified and
quantified by mass spectrometry. The results clearly demonstrate that both PC1 and PC2 mediate
the formation of SP and Tachykinin 58-71, an important SP precursor, with over 50% reduction
of the rate of formation in mutant PC 1 and PC2 mouse S9 spinal cord fractions. The results
obtained revealed that PC1 and PC2 are involved in the C-terminal processing of protachykinin
peptides and suggest a major role in the maturation of the protachykinin-1 protein.
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