Proteolytic Inactivation of Substance P and Neurokinin A in the Longitudinal Muscle Layer of Guinea Pig Small Intestine

R. Nau, G. Schäfer, C. F. Deacon, T. Cole, D. V. Agoston, J. M. Conlon

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Abstract: Membrane vesicles, showing a 21 ± 2‐fold enrichment in the activity of 5′‐nucleotidase and a 11 ± 4‐fold enrichment in the activity of angiotensin‐converting enzyme relative to homogenate, were prepared from the myenteric plexus‐containing longitudinal muscle layer of guinea pig ileum. Incubation of the vesicles with substance P and neurokinin A led to degradation of the peptides, and metabolites were isolated by reverse‐phase HPLC and identified by amino acid composition. Cleavages of substance P between Glu6‐Phe7, Phe7‐Phe8, and Gly9‐Leu10 and of neurokinin A between Gly8‐Leu9 were observed and could be inhibited in a dose‐dependent manner by phosphoramidon, an inhibitor of neutral endopeptidase 24.11. Formation of these metabolites was not completely inhibited by this agent, indicating that a phosphoramidon‐insensitive form of endopeptidase 24.11 was present in the gut. Substance P was resistant to degradation by aminopeptidases, but neurokinin A was a substrate for bestatin‐sensitive aminopeptidase(s), so that the neurokinin A (3–10) fragment represented the predominant metabolite in the chromatograms. The rate of formation of all the metabolites was not inhibited by ena‐lapril and not enhanced by an increased Cl concentration, indicating that angiotensin‐converting enzyme was unimportant in the degradation process. Degradation of neurokinin A by the vesicles (Km 30 μM; Vmax 7.2 ±0.8 nmol min−1 mg of protein−1) was more rapid than degradation of substance P (Km 25 μM; Vmax 4.4 ± 0.4 nmol min−1 mg of protein−1).

Original languageEnglish
Pages (from-to)856-864
Number of pages9
JournalJournal of Neurochemistry
Issue number3
Publication statusPublished (in print/issue) - Sept 1986


  • Aminopeptidase
  • Endopeptidase 24.11
  • Membrane vesicle
  • Neurokinin A
  • Substance P


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