Peptides play many important physiological roles in most organisms. Neuropeptides and peptide hormones function in cell-cell signaling and are involved with a wide variety of biological functions including feeding and body weight regulation, fear, anxiety, pain, circadian rhythms, memory, reward mechanisms, and many others. We have discovered a number of novel peptides using mass spectrometry-based peptidomic techniques. Some of these are neuropeptides that function in cell-cell signaling that control feeding/body weight. Many of the other novel peptides are produced from cytosolic proteins, and not from secretory pathway proteins that are the precursors of classical neuropeptides. Some of the peptides derived from cytosolic proteins are secreted and bind to extracellular receptors; these are putative “non-classical” neuropeptides, a novel class of cell-cell signaling molecule. Further studies are aimed at understanding the mechanisms by which these peptides are produced, secreted, and regulated, with the overall goal to identify the peptides' functions.
In addition to peptides, we are also interested in enzymes that modify peptides/proteins. Our laboratory has discovered a dozen different carboxypeptidases and we are currently working towards determining their functions. One carboxypeptidase, which we named carboxypeptidase E, is responsible for the formation of many peptide hormones (such as insulin) and neuropeptides (such as enkephalin). We identified a strain of mouse (named fat/fat) that does not produce active carboxypeptidase E due to a point mutation; these mice are obese, sterile, hyperglycemic, and have neurological impairments. In addition to neuropeptide processing enzymes, several other cellular peptidases are being studied in the laboratory. Current projects use peptidomics and other techniques to identify the physiological function of the peptidase. Some of the enzymes being studied are the cytosolic carboxypeptidases; these enzymes modify tubulin (and possibly other proteins) by removing amino acids from the C-terminus and/or side-chains, thereby altering the properties of tubulin. Mice lacking cytosolic carboxypeptidase 1 show abnormal movement due to neurodegeneration of cerebellar Purkinje cells. Another enzyme currently being studied is carboxypeptidase A6; humans with mutations in this enzyme develop epilepsy. We are studying the role of carboxypeptidase A6 in animal models, with a focus on understanding how mutations in the protein lead to epilepsy.
Salzmann, A., Guipponi, M., Lyons, P.J., Fricker, L.D., Sapio, M., Lambercy, C., Buresi, C., Bencheikh, B.O.A., Lahjouji, F., Ouazzani, R., Crespel, A., Chaigne, D., and Malafosse, A., Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy, Hum. Mutat., 33:124-35, 2012.
Gelman, J.S., Wardman, J.H., Bhat, V.B., Gozzo, F.C., and Fricker, L.D., Quantitative peptidomics to measure neuropeptide levels in animal models relevant to psychiatric disorders, Methods Mol Biol., 829:487-503, 2012.
Berezniuk, I., Vu, H.T., Lyons, P.J., Sironi, J.J., Xiao, H., Burd, B., Setou, M., Angeletti, R.H., Ikegami, K., and Fricker, L.D., Cytosolic carboxypeptidase 1 is involved in processing of alpha-tubulin and beta-tubulin, J. Biol. Chem., 287:6503-17, 2012.
Fricker, L.D., Gelman, J.S., Castro, L.M., Gozzo, F.C., and Ferro, E.S., Peptidomic analysis of HEK293T cells: Effect of the proteasome inhibitor epoxomicin on intracellular peptides, J. Proteome Res., 11:1981-1990, 2012.
Fricker, L.D., Neuropeptides and Other Bioactive Peptides: From Discovery to Function, Morgan Claypool Publishers, 2012, ISBN 978-1-61504-521-1.
Fricker, L.D., Mass spectrometry of immunolabeled neurons—the best of both techniques, Chem. & Biol., 19:931-2, 2012.
Sapio, M., Salzmann, A., Vessaz, M., Crespel, A., Lyons, P.J., Malafosse, A., and Fricker, L.D., Naturally occurring carboxypeptidase A6 mutations: Effect on enzyme function and association with epilepsy. J. Biol. Chem., 287:42900-9, 2012. (PMCID: PMC3522286)
Fricker, L.D. and Devi, L.A., Transmitters and peptides: Basic principles. In: Neuroscience in the 21st Century (D. Pfaff, ed.), Springer, pp. 1487-1504, 2013.
Fricker, L.D. and Devi, L.A., Transmitter and peptide receptors: Basic principles. In: Neuroscience in the 21st Century (D. Pfaff, ed.), Springer, pp. 1505-1524, 2013.
Gelman, J.S., Sironi, J., Berezniuk, I., Dasgupta, S., Castro, L.M., Gozzo, F.C., Ferro, E.S., and Fricker, L.D., Alterations of the cellular peptidome in response to the proteasome inhibitor bortezomib. PLoS ONE 8(1): e53263, 2013. (PMCID: PMC3538785)
Fricker, L.D. and Gomis-Rüth, F.X., Carboxypeptidase A4. In: Handbook of Proteolytic Enzymes, Third Edition, (N.D. Rawlings, G.S. Salvesen, eds.) Oxford: Academic Press, pp. 1307-1310, 2013.
Fricker, L.D., Carboxypeptidase A5. In: Handbook of Proteolytic Enzymes, Third Edition, (N.D. Rawlings, G.S. Salvesen, eds.) Oxford: Academic Press, pp. 1315-1317, 2013.
Fricker, L.D. and Lyons, P.J., Carboxypeptidase A6. In: Handbook of Proteolytic Enzymes, Third Edition, (N.D. Rawlings, G.S. Salvesen, eds.) Oxford: Academic Press, pp. 1318-1321, 2013.
Fricker, L.D., Metallocarboxypeptidase D. In: Handbook of Proteolytic Enzymes, Third Edition, (N.D. Rawlings, G.S. Salvesen, eds.) Oxford: Academic Press, pp. 1353-1357, 2013.
Fricker, L.D., Carboxypeptidase E. In: Handbook of Proteolytic Enzymes, Third Edition, (N.D. Rawlings, G.S. Salvesen, eds.) Oxford: Academic Press, pp. 1342-1345, 2013.
Fricker, L.D., Carboxypeptidase Z. In: Handbook of Proteolytic Enzymes, Third Edition, (N.D. Rawlings, G.S. Salvesen, eds.) Oxford: Academic Press, pp. 1346-1347, 2013.
Berezniuk, I., Sironi, J., Wardman, J.H., Pasek, R.C., Berbari, N.F., Yoder, B.K., and Fricker, L.D., Quantitative peptidomics of Purkinje cell degeneration mice. PLoS One, 8:e60981, 2013. (PMCID: PMC3620535)
Rodriguiz, R.M., Wilkins, J.J., Biswas, R., Berezniuk, I., Fricker, A.D., Fricker, L.D., and Wetsel, W.C., Emergence of anxiety-like behaviors in depressive-like Cpefat/fat mice. Int. J. Neuropsychopharm., 16:1623-1634, 2013.
Fricker, L.D., Carboxypeptidase E and D, In: Handbook of Biologically Active Peptides, (ed. A. Kastin), Academic Press, in press, 2013.
Wardman, J.H, and Fricker, L.D., Peptidomics of Mice Lacking Peptide Processing Enzymes, In: Handbook of Biologically Active Peptides, (ed. A. Kastin), Academic Press, in press, 2013.
Gelman, J.S., Dasgupta, S, Berezniuk, I., and Fricker, L.D., Analysis of peptides secreted from mouse brain tissue. Biochim. Biophys. Acta, In press, 2013.
(publication list last updated 7/12/13)
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