Signal Transduction at Neuropeptide Receptors:
Our laboratory studies the neuropeptide calcitonin gene-related peptide (CGRP). Originally discovered as an alternatively-spliced variant of the calcitonin mRNA, CGRP is one of the most potent vasodilators known. As a vasodilator, CGRP has both peripheral and central effects. One of the most notable effects of CGRP is its causative effect of migraine on the cerebral vasculature, and stable synthetic antagonists have been recently developed and are in Stage III clinical trials for migraine treatment. CGRP also suppresses immune function, is involved in pain perception, and has further central role in the development of tolerance to opiates.
Recently, we have discovered that CGRP is a potent stimulator of glioma and metastatic breast cancer tumor cell growth. In collaboration with Dr. Edward Brown (Biomedical Engineering) we have observed remarkable increases in tumor cell growth rates in response to CGRP incubation. These data suggest that the CGRP receptor system represents an important new target for these types of cancer for which therapy is currently limited.
The CGRP receptor is unique for G protein-coupled receptors (GPCR) in that it requires three proteins for function: calcitonin-like receptor (CLR), a stereotypical GPCR with 7 hydrophobic transmembrane domains; receptor activity modifying protein (RAMP1), a single transmembrane accessory protein that targets CLR to the cell surface and confers pharmacologic specificity, and CGRP receptor component protein (RCP) which couples the CLR/RAMP1 complex to the cellular signaling pathway.
Our laboratory is investigating the mechanism of RCP action by: (1) determining the molecular/ biochemical requirements for RCP function, (2) determining the proteins that interact with RCP in a functional receptor complex using proteomic strategies, (3) determining the role of RCP and CGRP in vivo, using targeted homologous recombination to generate transgenic RCP knockout mice.
In addition, we are applying the biochemical reagents made in the first three areas of interest to directly test the role of the CGRP receptor in glioma and breast cancer proliferation, with the long-term goal of identifying novel protein interactions required for CGRP receptor function as targets for future anti-cancer drug development.
Ma W, Chabot JG, Powell KJ, Jhamandas K, Dickerson IM, Quirion R. (2003) "Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems." Neuroscience. 120(3):677-94.
Lai, Y.C., Shaftel, S.S,, Miller, J.N., Tallents, R.H., Pinkert, C.A., Olschowka, J.A., Dickerson, I.M., Puzas, J. E., O'Banion, M. K., Kyrkanides, S. (2006). "Intraarticular induction of interleukin-1beta expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain" Arthritis Rheum. 54:1184-1197.
Zhang, Z., Dickerson, I.M., Russo, A.F. (2006) "CGRP Receptor Activation by RAMP1 Gene Transfer to Vascular Smooth Muscle Cells" Endocrinol. 147(4):1932-40.
Tolun, A.A., Dickerson, I.M., Malhotra, A. (2006). "Overexpression and purification of human calcitonin gene-related peptide-receptor component protein in Escherichia coli". Protein Expr Purif. 52:167-174.
Glaser, S., Ueno, Y., DeMorrow, S., Chiasson, V., Katki, K., Venter, J., Francis, H., Dickerson, I.M., DiPette, D., Supowit, S., Alpini, G. (2007) "Knockout of Alpha Calcitonin Gene-Related Peptide Prevents Cholangiocyte Proliferation Induced by Extrahepatic Bile Duct Obstruction" Lab. Invest;87(9):914-26.
Morara S, Wang LP, Filippov V, Dickerson IM, Grohovaz F, Provini L, Kettenmann H. (2008). "Calcitonin gene-related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and in Bergmann glial cells from cerebellar slices" Eur J Neurosci. 28:2213-20.