Modulation of endopeptidase activity by calcitonin gene related peptide: a mechanism affecting substance P action?
Peptides with hormonal or neuronal activity are derived by enzymatic processing from pro-hormones, which by themselves are biologically inert. Processing and other enzymatic conversions may occur step-wise, leading to the formation of a cascade of biologically active (or inactive) peptides. The neurokin in substance P is known to be metabolically transformed both by amino- and endopeptidases. More N-terminal substance (1-7) has been found than C-terminal (2-11 to 5-11) fragments in various CNS areas. The substance P (1-7) fragment also shows biological activity e.g., providing analgesia, lowering blood pressure, inhibiting aggressive behavior and (in contrast to substance P) inhibiting grooming behavior. An endopeptidase generating substance P (1-7) and to a lesser extent, substance (1-8), has been isolated and characterized from human cerebrospinal fluid (CSF) and bovine spinal cord, as a metalloenzyme with essential SH-groups. Substance P co-exists with calcitonin gene related peptide (CGRP) in a large population of non-myelinated primary afferent ('pain') fibers. Intrathecal injection of substance P causes behavioral and physiological responses which are potentiated and prolonged by CGRP. It was found that CGRP competes with substance P for the endopeptidase. It is suggested that the main action of CGRP in the spinal cord is to inhibit substance P degradation.
Nyberg
F
F
Department of Pharmacology, Uppsala, Sweden.
Le Grevés
P
P
Terenius
L
L
D000595:Amino Acid Sequence; D000818:Animals; D015740:Calcitonin Gene-Related Peptide; D010450:Endopeptidases / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics* / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D013373:Substance P / Q000502:physiology*; D013379:Substrate Specificity
D009479:Neuropeptides; D013373:Substance P; D010450:Endopeptidases; D015740:Calcitonin Gene-Related Peptide