Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates

Hambrook, Jean M.; Morgan, Barry A.; Rance, Michael J.; Smith, C. F. C.

doi:10.1038/262782a0

Cited by 507 publications

(92 citation statements)

References 9 publications

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“…There is some evidence that Leu-enkephalin is cleaved by a CP within the brain; a small amount of Leu was released upon incubation of Leu-enkephalin with brain membranes (39). However, previous studies did not specifically examine olfactory bulb (37,38), and it is possible that CPA6 plays a major role in enkephalin degradation in this brain region. Interestingly, proenkephalin mRNA is present at high levels in the mouse olfactory bulb (Allen Brain Atlas), and enkephalin peptides and opioid receptors have also been detected in this brain region (40,41).…”

Section: Discussionmentioning

confidence: 85%

Characterization of Carboxypeptidase A6, an Extracellular Matrix Peptidase

Lyons

Callaway

Fricker

2008

Journal of Biological Chemistry

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Carboxypeptidase A6 (CPA6) is a member of the M14 metallocarboxypeptidase family that is highly expressed in the adult mouse olfactory bulb and broadly expressed in embryonic brain and other tissues. A disruption in the human CPA6 gene is linked to Duane syndrome, a defect in the abducens nerve/lateral rectus muscle connection. In this study the cellular distribution, processing, and substrate specificity of human CPA6 were investigated. The 50-kDa pro-CPA6 is routed through the constitutive secretory pathway, processed by furin or a furinlike enzyme into the 37-kDa active form, and secreted into the extracellular matrix. CPA6 cleaves the C-terminal residue from a range of substrates, including small synthetic substrates, larger peptides, and proteins. CPA6 has a preference for large hydrophobic C-terminal amino acids as well as histidine. Peptides with a penultimate glycine or proline are very poorly cleaved. Several neuropeptides were found to be processed by CPA6, including Met-and Leu-enkephalin, angiotensin I, and neurotensin. Whereas CPA6 converts enkephalin and neurotensin into forms known to be inactive toward their receptors, CPA6 converts inactive angiotensin I into the biologically active angiotensin II. Taken together, these data suggest a role for CPA6 in the regulation of neuropeptides in the extracellular environment within the olfactory bulb and other parts of the brain.

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Section: Discussionmentioning

confidence: 85%

Characterization of Carboxypeptidase A6, an Extracellular Matrix Peptidase

Lyons

Callaway

Fricker

2008

Journal of Biological Chemistry

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“…Three distinct peptidases, aminopeptidase (12), pep tidyl dipeptidase A (13) and enkephalinase (14), are known to catalyze the enzymatic degradation of Met-enk. A mixture of an aminopeptidase inhibitor, a peptidyl dipeptidase A inhibitor and an enkephalinase inhibitor has been shown to completely protect Met-enk from degradation produced by incubation with either an ileal or a striatal membrane fraction from guinea pigs (15).…”

Section: Introductionmentioning

confidence: 99%

Effects of a Mixture of Peptidase Inhibitors (Amastatin, Captopril and Phosphoramidon) on Met-Enkephalin-, β-Endorphin-, Dynorphin-(l-13)- and Electroacupuncture-Induced Antinociception in Rats

Kishioka¹,

Miyamoto²,

Fukunaga³

et al. 1994

Japanese Journal of Pharmacology

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ABSTRACT-The effects of a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon, on methionine-enkephalin (Met-enk)-, j3-endorphin (p-end)-, dynorphin-(1 13) (Dyn) and electroacupuncture (EA)-induced antinociception were compared in rats. EA was performed by passing electric pulses (3 Hz, 0.1-msec duration, for 45 min) through acupuncture needles inserted into the Hoku point. The antinociceptive effect was estimated by the hind paw pressure test. The antinociceptive effects of Met-enk and p-end injected i.c.v. or Lt. and of Dyn injected i.t. were clearly potentiated by the PIs pretreated by the same administration routes as used for the injection of opioid peptides. The antinocicep tive effects of Met-enk, n-end and Dyn injected i.c.v. were also potentiated significantly by i.t.-PIs. PIs in jected into the periaqueductal gray (PAG) potentiated EA antinociception. However, the EA effect was not affected by i.t.-PIs and was rather attenuated by i.c.v.-PIs. These results suggest that: i) Met-enk hydro lyzing enzymes are involved in the degradation of not only Met-enk but also p-end and Dyn in the rat central nervous system; ii) Met-enk and n-end act on both supraspinal and spinal sites, while Dyn acts only on the spinal site; iii) EA antinociception is mediated by supraspinal Met-enk and/or n-end; and iv) an anti-opiate peptide system may be activated by EA stimulation, being susceptible to Met-enk hydrolyzing enzymes.

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“…The enzymatic degradation of enkephalins occurs most rapidly at Tyrl-Gly s in rat brain homogenates [16] and in plasma [17]; and also at Glya-Phe 4 by a dipeptidyl carboxypeptidase, enkephalinase [18]. Substitution of D-Ala s for Gly s gives a peptide with good agonist properties having a longer duration of action [16].…”

Section: Resultsmentioning

confidence: 99%

Dehydro‐enkephalins: Receptor binding activity of unsaturated analogs of Leu⁵‐enkephalin

1981

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Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates

Cited by 507 publications

References 9 publications

Characterization of Carboxypeptidase A6, an Extracellular Matrix Peptidase

Characterization of Carboxypeptidase A6, an Extracellular Matrix Peptidase

Effects of a Mixture of Peptidase Inhibitors (Amastatin, Captopril and Phosphoramidon) on Met-Enkephalin-, β-Endorphin-, Dynorphin-(l-13)- and Electroacupuncture-Induced Antinociception in Rats

Dehydro‐enkephalins: Receptor binding activity of unsaturated analogs of Leu⁵‐enkephalin

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Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates

Cited by 507 publications

References 9 publications

Characterization of Carboxypeptidase A6, an Extracellular Matrix Peptidase

Characterization of Carboxypeptidase A6, an Extracellular Matrix Peptidase

Effects of a Mixture of Peptidase Inhibitors (Amastatin, Captopril and Phosphoramidon) on Met-Enkephalin-, β-Endorphin-, Dynorphin-(l-13)- and Electroacupuncture-Induced Antinociception in Rats

Dehydro‐enkephalins: Receptor binding activity of unsaturated analogs of Leu5‐enkephalin

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Dehydro‐enkephalins: Receptor binding activity of unsaturated analogs of Leu⁵‐enkephalin