Neuroendocrine peptides serve many important functions in cell-cell signalling. The discovery of bioactive peptides has typically required difficult purification procedures. We have developed a novel technique that uses a single affinity column step to isolate peptides that are substrates of carboxypeptidase E, one of the key enzymes involved in the processing of peptide precursors into the mature forms. Using this technique we sequenced over 100 peptides. Many of these are known peptides, which validates the approach. A large number of the peptides we identified represent novel cleavage products of known neuroendocrine proteins. In addition, we identified five peptides which are derived from a single novel precursor, termed proSAAS. Based on preliminary data, we hypothesize that proSAAS is an endogenous inhibitor of prohormone convertase I (a neuropeptide processing enzyme), and that smaller fragments of proSAAS have additional functions in cell-cell signalling. To test this hypothesis, we will pursue the following specific aims:
Aim 1 will investigate the processing of proSAAS in rat brain and other tissues.
Aim 2 will investigate the distribution of pr0SAAS and proSAAS-derived peptides in rat brain and other tissues using immunohistochemistry. .
Aim 3 will study proSAAS and the proSAAS-derived peptides as enzyme substrates and inhibitors.
Aim 4 will explore functions for pr0SAAS-derived peptides in cell-cell signalling. The studies described in this application will advance our knowledge of peptide processing. The evidence that pr0SAAS functions as an endogenous inhibitor of prohormone convertase 1 implies that pr0SAAS will be a factor in the processing of numerous peptides, and thus the proposed studies are likely to be relevant to human health and disease; neuroendocrine peptides have been implicated in the regulation of pain, memory, feeding, metabolism, circadian rhythms, anxiety, and many other behaviors.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZRG1-MDCN-5 (01))
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Rapaka, Rao
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Albert Einstein College of Medicine
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Fricker, Lloyd D; Devi, Lakshmi A (2018) Orphan neuropeptides and receptors: Novel therapeutic targets. Pharmacol Ther 185:26-33
Berezniuk, Iryna; Rodriguiz, Ramona M; Zee, Michael L et al. (2017) ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine. J Neurochem 143:268-281
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
Dasgupta, Sayani; Yang, Ciyu; Castro, Leandro M et al. (2016) Analysis of the Yeast Peptidome and Comparison with the Human Peptidome. PLoS One 11:e0163312
Lopes, Mark William; Sapio, Matthew R; Leal, Rodrigo B et al. (2016) Knockdown of Carboxypeptidase A6 in Zebrafish Larvae Reduces Response to Seizure-Inducing Drugs and Causes Changes in the Level of mRNAs Encoding Signaling Molecules. PLoS One 11:e0152905
Fricker, Lloyd D (2015) Limitations of Mass Spectrometry-Based Peptidomic Approaches. J Am Soc Mass Spectrom 26:1981-91
Sapio, Matthew R; Vessaz, Monique; Thomas, Pierre et al. (2015) Novel carboxypeptidase A6 (CPA6) mutations identified in patients with juvenile myoclonic and generalized epilepsy. PLoS One 10:e0123180
Dasgupta, Sayani; Fishman, Michael A; Mahallati, Hana et al. (2015) Reduced Levels of Proteasome Products in a Mouse Striatal Cell Model of Huntington's Disease. PLoS One 10:e0145333
Sapio, Matthew R; Fricker, Lloyd D (2014) Carboxypeptidases in disease: insights from peptidomic studies. Proteomics Clin Appl 8:327-37
Wardman, Jonathan H; Fricker, Lloyd D (2014) ProSAAS-derived peptides are differentially processed and sorted in mouse brain and AtT-20 cells. PLoS One 9:e104232

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