A wide variety of proteins in neuronal, endocrine and immune tissues undergo proteolytic processing. Many of the resulting peptides are intercellular messengers. Neuroendocrine peptides are synthesized from precursor proteins. Post-translational processing of these precursors is a key step in the production of biologically active peptides. In the majority of cases this occurs by proteolysis of the precursors at `classical' cleavage sites by prohormone convertases. However, in a subset of cases bioactive peptides are generated by processing at `non-classical' cleavage sites. The peptidases responsible for these cleavages are not well explored. During the previous funding cycle we identified endothelin converting enzyme 2 (ECE2), a metallopeptidase, as a potential candidate since it exhibited functional properties that are consistent with such a role. Recently we found that ECE2 processes peptides in an endocytic compartment and this, in turn, affects receptor trafficking and signaling. This is intriguing since it raises a novel role for endosomal non-classical peptide processing in the modulation of receptor function. In this application we describe studies, using the opioid peptide-receptor system as a model, to systematically examine the emerging area of endocytic peptide processing by ECE2 and its impact on the activity of opioid receptors. Specific studies are:
Aim 1. To establish a role for ECE2 in regulating opioid receptor recycling and resensitization, Aim 2. To explore the functional consequences of peptide processing by ECE2, and Aim 3. To investigate the role of ECE2 in opioid receptor function in biological systems. These studies are highly significant since they question the dogma in the field that the action of the neuropeptides are terminated following endocytosis; we raise the intriguing possibility that some biologically active neuropeptides are generated post endocytosis and this affects the type and extent of signaling. These studies are also likely to have a high impact since we describe studies to generate pharmacological profiles for endogenous opioid ligands by defining their functional selectivity - an emerging area of research in the field. Finally, these studies will make a fundamental contribution by identifying novel pathways that regulate neuropeptide levels in vivo, thus opening novel therapeutic possibilities for the treatment of a variety of neuroendocrine disorders.

Public Health Relevance

This proposal describes studies on the regulation of neuropeptide levels and its impact on neuroendocrine receptor function. Using the opioid system (peptides and receptors) as a model, studies to specifically characterize alternative, non-classical pathways of generation of neuropeptides and the enzymes involved in this process are proposed. Due to the broad involvement of the opioid system in normal physiology and disease, the findings from the proposed studies would open new avenues for the development of novel therapeutics for the treatment of pain, addiction and other neuroendocrine disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026880-28
Application #
9637449
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Gnadt, James W
Project Start
1989-08-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
28
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Fricker, Lloyd D; Devi, Lakshmi A (2018) Orphan neuropeptides and receptors: Novel therapeutic targets. Pharmacol Ther 185:26-33
Lueptow, Lindsay M; Devi, Lakshmi A; Fakira, Amanda K (2018) Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders. Prog Mol Biol Transl Sci 159:1-25
Heimann, Andrea S; Gupta, Achla; Gomes, Ivone et al. (2017) Generation of G protein-coupled receptor antibodies differentially sensitive to conformational states. PLoS One 12:e0187306
Bobeck, Erin N; Gomes, Ivone; Pena, Darlene et al. (2017) The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning. Neuropsychopharmacology 42:2527-2536
Reckziegel, Patrícia; Festuccia, William T; Britto, Luiz R G et al. (2017) A novel peptide that improves metabolic parameters without adverse central nervous system effects. Sci Rep 7:14781
Pena, Darlene Aparecida; Andrade, Victor Piana de; Silva, Gabriela Ávila Fernandes et al. (2016) Rational design and validation of an anti-protein kinase C active-state specific antibody based on conformational changes. Sci Rep 6:22114
Gomes, Ivone; Sierra, Salvador; Devi, Lakshmi A (2016) Detection of Receptor Heteromerization Using In Situ Proximity Ligation Assay. Curr Protoc Pharmacol 75:2.16.1-2.16.31
Gomes, Ivone; Bobeck, Erin N; Margolis, Elyssa B et al. (2016) Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Sci Signal 9:ra43
Wardman, Jonathan H; Gomes, Ivone; Bobeck, Erin N et al. (2016) Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci Signal 9:ra55
Gupta, Achla; Gomes, Ivone; Bobeck, Erin N et al. (2016) Collybolide is a novel biased agonist of ?-opioid receptors with potent antipruritic activity. Proc Natl Acad Sci U S A 113:6041-6

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