Reduced levels of neurotransmitter-degrading enzyme PRCP promote obesity
Richard D. Palmiter
Richard D. Palmiter
Published July 20, 2009
Citation Information: J Clin Invest. 2009;119(8):2130-2133. https://doi.org/10.1172/JCI40001.
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Commentary

Reduced levels of neurotransmitter-degrading enzyme PRCP promote obesity

Abstract

The level of neurotransmitters present in the synaptic cleft is a function of the delicate balance among neurotransmitter synthesis, recycling, and degradation. While much is known about the processes controlling neurotransmitter synthesis and release, the enzymes that degrade peptide neurotransmitters are poorly understood. A new study in this issue of the JCI reveals the important role of neuropeptide degradation in regulating obesity (see the related article beginning on page 2291). Wallingford et al. provide evidence that, in mice, the enzyme prolylcarboxypeptidase (PRCP) degrades α-melanocyte–stimulating hormone (α-MSH) to an inactive form that is unable to inhibit food intake. Their studies indicate that PRCP expression promotes obesity, while inhibitors of the enzyme counteract obesity.

Authors

Richard D. Palmiter

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Figure 2

Processing of POMC to α-MSH.

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Processing of POMC to α-MSH. POMC is synthesized in brain, pituitary gla...
POMC is synthesized in brain, pituitary gland, and skin cells. It is transported into the secretory pathway and processed by several enzymes into a variety of active peptides, depending on the cells in which it is synthesized. In hypothalamic neurons, POMC processing to produce α-MSH is particularly important. The POMC precursor is first cut by proconvertase 1 (PC1) to release ACTH1–39, which is then cut by proconvertase 2 (PC2) to produce α-MSH1–17. Carboxypeptidase E (CPE) removes the basic amino acids (Lys-Lys-Arg) from the C terminus, and peptidyl α-amidating monooxygenase (PAM) converts the C-terminal glycine to an amide (NH2). The N terminus of α-MSH1–13 is acetylated by N-acetyltransferase (NAT) to produce mature, functional α-MSH1–13. After release from synaptic vesicles, α-MSH1–13 is inactivated (to α-MSH1–12) by the action of PRCP, the subject of the Wallingford et al. (8) study in this issue of the JCI.