Distribution of substance P-like immunoreactivity in the central nervous system of the rat—I. Cell bodies and nerve terminals

http://www.jbc.org/content/273/49/32730.full.pdf

Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation.

There is both theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct fropm angiotensin coverting enzyme (ACE), might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional and subcellular distributions as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this enzyme further, we have designed a potent and specific enkephalinase inhibitor. We report here that this compound, thiorphan [(DL-3-mercapto-2-benzylpropanoyl)-glycine; patent no. 8008601] protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration. In addition, thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors.

The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice

CONSIDERABLE evidence now exists to suggest that the endogenous opioid pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) function as neurotransmitters in the central nervous system. A correlate of this hypothesis is that a specific inactivation mechanism must operate in the vicinity of opiate receptors to turn off rapidly the enkephalin signal. Indeed recent studies have shown that the pentapeptides are subject to extremely rapid inactivation in various tissues, occurring primarily by cleavage of the Tyr–Gly amide bond1–5. This feature accounts for the short-lasting biological activity of these peptides, contrasting with the potent activity of synthetic analogues such as (D-Ala2)-Met-enkephalinamide in which this bond is protected6. However, many tissues including brain contain a spectrum of peptidases with low specificities and affinities7 and no evidence has been yet provided for the involvement of a specific enzyme in the regulation of enkephalinergic transmission. We now report the presence of a high-affinity peptidase in a particulate fraction of mouse striatum splitting the Leu-enkephalin molecule with release of a tripeptide fragment (Tyr-Gly-Gly) and exhibiting definite substrate specificity. The marked and selective increase in the activity of this peptidase in the striatum of mice chronically treated with morphine suggests that it might be associated with enkephalinergic transmission.

High-affinity enkephalin-degrading peptidase in brain is increased after morphine

Neville Marks

Papers

On the degradation of enkephalins and endorphins by rat and mouse brain extracts

Co-identity of brain angiotensin converting enzyme with a membrane bound dipeptidyl carboxypeptidase inactivating Met - enkephalin.

Breakdown of somatostatin and substance P by cathepsin D purified from calf brain by affinity chromotography

Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide

Characterization of a distinct membrane bound dipeptidyl carboxypeptidase inactivating enkephalin in brain.