Publications

• Angiotensin-converting enzyme gates brain circuit-specific plasticity via an endogenous opioid.

  Trieu B.H., Remmers B.C., Toddes C., Brandner D.D., Lefevre E.M., Kocharian A., Retzlaff C.L., Dick R.M., Mashal M.A., Gauthier E.A., Xie W., Zhang Y., More S.S., Rothwell P.E.

  Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkeph ... >> More

  Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction. << Less

  Science 2022:eabl5130-eabl5130(2022) [PubMed] [EuropePMC]

• Separate metabolic pathways for Leu-enkephalin and Met-enkephalin-Arg(6)-Phe(7) degradation by rat striatal synaptosomal membranes.

  Benuck M., Berg M.J., Marks N.

  Metabolism of Leu-enkephalin and Met-enkephalin-Arg(6)-Phe(7) was studied using synaptosomal plasma membranes prepared from rat corpus striatum and whole brain. Cleavage of the pentapeptide was mediated largely by an aminopeptidase leading to the release of Tyr and Gly-Gly-Phe-Leu. Bestatin, an am ... >> More

  Metabolism of Leu-enkephalin and Met-enkephalin-Arg(6)-Phe(7) was studied using synaptosomal plasma membranes prepared from rat corpus striatum and whole brain. Cleavage of the pentapeptide was mediated largely by an aminopeptidase leading to the release of Tyr and Gly-Gly-Phe-Leu. Bestatin, an aminopeptidase inhibitor, prevented the release of Tyr and the tetrapeptide, but not secondary cleavage at the Gly Phe site leading to the release of Tyr-Gly-Gly and Phe-Leu. Cleavage at the latter site was inhibited by low concentrations of Thiorphan, an inhibitor of a non-aminopeptidase enkephalinase. MK-421, an inhibitor of the angiotensin converting enzyme, acted only at high substrate concentrations of Leu-enkephalin, indicating that the converting enzyme has a relatively low affinity for the pentapeptide. In contrast to the pentapeptide the major products found upon incubation of heptapeptide with synaptosomal plasma membrane were Arg-Phe and Met-enkephalin. Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. This pathway may represent a mechanism for the formation of Met-enkephalin from larger precursors present in striatum and other regions of the central nervous system. << Less

  Neurochem. Int. 4:389-396(1982) [PubMed] [EuropePMC]