Biomedical Engineering Reference
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substrate have been reported. Further supporting a role for DP4 regulation in
the cardiovascular system is the demonstrated cleavage of plasma B-type
natriuretic peptide (BNP) by DP4, resulting in the release of its truncated form,
BNP (3-32). 161 BNP (3-32), known also as des-SerPro-BNP, has been detected
in plasma of patients with heart failure. 209 BNP is one of two natriuretic
secreted by the heart
that are
involved in cardiovascular
homeostasis. 210
1.6.3 Nociception and Neuropsychiatric Disorders
Substance P is a widespread neuropeptide implicated in numerous roles,
including nociception, mood and anxiety disorders, aggressive behavior, and
immunity. 211-214 It was demonstrated as early as 1978 that DP4 can cleave
substance P, 166 and sequential DP4 cleavage results in the generation of sub-
stance P (3-11) , then substance P (5-11) . 167 Alterations in the level of serum DP4
activity have been associated with a number of psychiatric disorders such as
depression, anxiety, schizophrenia, and anxiety. 67,215 DP4 cleavage of sub-
stance P activity may be involved in these processes, but it is important to note
that the levels of serum PEP activity, also capable of cleaving substance P, are
also altered in these disorders. 216,217 Recently, pre-incubation of substance P
with a DP4-overexpressing glioma cell line was found to lead to a loss of
substance P signaling via intracellular calcium mobilization. 218 DP4 cleavage
modulation of pain is further discussed below.
Endomorphin-1 and endomorphin-2 are endogenous opioid peptides,
expressed widely in the central nervous system, having key roles in nociception,
and they participate in inflammatory disorders such as rheumatoid arthritis,
osteoarthritis, and experimental arthritis (reviewed by Jessop et al. 219 ). Endo-
morphin-1 was identified as being a DP4 substrate based on the increased
stability of endomorphin-1 in the presence of porcine buccal mucosa by
Diprotin-A (Ile-Pro-Ile), a competitive DP inhibitor. 179 Diprotin-A is also
capable of inhibiting PEP, 220 aminopeptidase N, 220 and DP8/DP9 21 activity,
making it possible that DP4 is not the enzyme responsible for the observed
cleavage. DP2 is an unlikely candidate due its poor inhibition by Diprotin A
with K i of 435 000 nM compared to a K i of 4250 nM for the inhibition of
DP4. 25 Janecka et al. provide a detailed review on the degradation of endo-
morphins by DP4 and other proteases including aminopeptidase M, carbox-
ypeptidase Y, and proteinase A. 221 DP4 has been implicated in the modulation
of nociception via cleavage of endogenous substrates, endomorphin-1, endo-
morphin-2, and substance P. 177,222 Inhibition of DP4 activity with Ala-Pyrro-
lidonyl-2-nitrile in mice has been found to lead to enhanced analgesic effects
of exogenously administered endomorphin-2. 177 Morphiceptin, similar in
sequence to the endomorphins and a reported analog of b-casomorphin, is
another endogenous opioid peptide that acts as a highly potent and selective
agonist for the m-opioid receptor known for its roles in pain perception. 223 In
situ perfusion in rats genetically deficient in DP4 revealed a significant increase
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