Reduced levels of neurotransmitter-degrading enzyme PRCP promote a lean phenotype. [corrected]

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 alpha-melanocyte-stimulating hormone (alpha-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.

Figure 1. Neural circuitry in the hypothalamus that regulates feeding and metabolism.

(A) The POMC pathway. Activation of neurons that make POMC inhibits feeding and stimulates metabolism. Under conditions of energy excess, POMC neurons are activated by circulating hormones and neurotransmitters. POMC neurons process the POMC precursor protein to α-MSH_1–13 within the secretory pathway, as shown in Figure 2. When these neurons are activated, they release α-MSH_1–13 into the synaptic cleft, where it can bind to melanocortin receptors (MC4R) on postsynaptic cells located in several brain regions. Mutations in genes responsible for making α-MSH or receiving the α-MSH signal result in obesity. The action of α-MSH_1–13 is terminated by the action of PRCP (the present study, ref. 8), which is presumably released from cells in the postsynaptic region; however, the identity of the cells that make PRCP and its cellular/extracellular localization are not currently known. The activity of PRCP thus puts a brake on α-MSH signaling; mice that lack PRCP are lean because they have excessive α-MSH signaling. (B) Activation of neuropeptide Y/agouti-related protein (NPY/AgRP) neurons counteracts the activity of POMC neurons. When energy balance is low, e.g., during starvation, signaling by the expression of POMC is reduced and the activity of POMC neurons is inhibited by the neighboring NPY/AgRP neurons that become activated and release NPY, AgRP, and GABA. NPY and AgRP are also neuropeptides that are processed from larger precursor proteins. NPY acts on G protein–coupled receptors that couple to Gαi and hence counter the action of α-MSH_1–13, which acts on Gαs-linked receptors; AgRP binds to the MC4R and prevents α-MSH signaling; and GABA, acting on ionotrophic GABA_A receptors, hyperpolarizes the POMC and postsynaptic neurons, thereby reducing their activity.

Figure 2. Processing of POMC to α-MSH.

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 ACTH_1–39, which is then cut by proconvertase 2 (PC2) to produce α-MSH_1–17. 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-MSH_1–13 is acetylated by N-acetyltransferase (NAT) to produce mature, functional α-MSH_1–13. After release from synaptic vesicles, α-MSH_1–13 is inactivated (to α-MSH_1–12) by the action of PRCP, the subject of the Wallingford et al. (8) study in this issue of the JCI.