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Targeting of Neuronal ProteinsSynaptic transmission requires spatial assembly of neurotransmitter receptors and associated signal transduction machinery at synaptic sites and the precise patterning of dendritic processes. Targeting of proteins to the synapse is a dynamic process. in which there is a balance of assembly and disassembly of proteins at synaptic homeostasis. In fact. when learning occurs. recruitment of existing and newly synthesized proteins to the synapse is increased. In contrast. when disassembly of synaptic signaling molecules occurs faster than assembly. homeostasis is lost and disease states such as Alzheimer's Disease occur in which synaptic transmission is compromised. An important long-term goal our work is to understand how synaptic targeting of proteins is perturbed in pathophysiological states. Our most recent studies focus on dendrite branching. The amount of branches that a dendrite. or input center of a neuron. contains is thought to be directly related to learning and memory. In fact. in a number of learning disorders. such as autism. Rett Syndrome. Down Syndrome. and Alzheimer's Disease. patients show a reduced number of dendrite branches. These patients also often show alterations in the metabolism. or breakdown. of a class of compounds called purines. My laboratory has recently discovered that cypin regulates the number of dendrite branches in areas of the brain related to learning and memory (Akum et al.. 2004). We have found that cypin promotes microtubule assembly and that branching in vivo correlates with cypin's activity as an enzyme involved in purine metabolism. The ultimate goal would be to be able to develop pharmaceutical agents to help patients with autism. Rett Syndrome. Down Syndrome. Alzheimer's Disease and other disorders to increase memory. Selected PublicationsFernández, J.R. and Firestein, B.L. (2008) Novel pharmacological targets to control dendritic branching and growth during neuronal development. Central Nervous System Agents in Medicinal Chemistry 8: 100-106. Kutzing, M.K. and B.L. Firestein (2008) Altered uric acid levels and disease states. J Pharmacol Exp Ther 324: 1-7. Hadzimichalis, N.M., S.S. Baliga, R. Golfetti, K.M. Jaques, B.L. Firestein and G.F. Merrill (2007) Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway. Am J Physiol Heart Circ Physiol 293: H3348-55. Jiang, X., P.C. Georges, B. Li, Y. Du, M.K. Kutzing, M.L. Previtera, N.A. Langrana, and B.L. Firestein (2007) Cell growth in response to mechanical stiffness is affected by neuron-astroglia interactions, The Open Neuroscience Journal 1: 7-14. Fernandez, J.R., Welsh, W.J. and Firestein, B.L. Structural characterization of the zinc binding domain in Cytosolic PSD-95 interactor (CYPIN): Role of zinc binding in guanine deamination and dendrite branching. (2007) Proteins: Structure, Function, and Bioinformatics, in press. Chen, H.X. and Firestein, B.L. (2007) Cypin acts downstream of RhoA to regulate dendrite branching in hippocampal neurons. Journal of Neuroscience:7(31):8378-86. Du Y, Chen CP, Tseng CY, Eisenberg Y, Firestein BL. (2007) Astroglia-mediated effects of uric acid to protect spinal cord neurons from glutamate toxicity. Glia. 55(5):463-72. Charych, E.I. *, Akum, B.F. *, Goldberg, J.S., Jörnsten, R.J., Rongo, C., Zheng, J.Q. and Firestein, B.L. (2006) Activity-independent regulation of dendrite patterning by postsynaptic density protein PSD-95. Journal of Neuroscience 26(40):10164-76. (*equal contributors) Van den Bergh G. Clerens S. Firestein BL. Burnat K. Arckens L. (2006) Development and plasticity-related changes in protein expression patterns in cat visual cortex: A fluorescent two-dimensional difference gel electrophoresis approach. Proteomics 6(13):3821-32. Chen. M.*. Lucas. K.G.*. Akum. B.F.. Balasingam. G.. Stawicki. T.M.. Provost. J.M.. Riefler. G.M.. Jörnsten. R.J. and Firestein. B.L. (2005) A novel role for snapin in dendrite patterning: Interaction with cypin. Molecular Biology of the Cell 16:5103-5114. (*equal contributors) Xu. B.. Wratten. N.. Charych. E.I. Buyske. S.. Firestein. B.L.. and Brzustowicz. L.M. (2005) Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder. PLoS Medicine 2(9):e263. Akum. B.F.. Chen. M.*. Gunderson. S.I.*. Riefler. G.M.. Scerri-Hansen. M.M. and Firestein. B.L. (2004) Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly.Nature Neuroscience. 7:145-152. (*equal contributors) Riefler. G.M.. Balasingam. G.*. Lucas. K.G.*. Wang. S.. Hsu. S.C. and Firestein. B.L. (2003) Sec-8 binds to PSD-95: A novel interaction regulated by cypin. Biochemical Journal 373:49-55. (*equal contributors) Zimmerman. C.. K. C. Klein. P. K. Kiser. A. R. Singh. B. L. Firestein. S. C. Riba. and J. R. Lingappa. (2002) Identification of a host protein essential for assembly of immature Human Immunodeficiency Virus type 1 capsids. Nature. 415(6867):88-92. Riefler. G.M. and Firestein. B.L. (2001) Binding of nNOS to CtBP changes the localization of CtBP from the nucleus to the cytosol. A Novel function for targeting by the pdz domain of nNOS. The Journal of Biological Chemistry. 276(51):48262-48268. Firestein. B.L. and Rongo. C. (2001) DLG-1 Is a MAGUK Similar to SAP97 and Is Required for Adherens Junction Formation. Molecular Biology of the Cell. 12(11):3465-3475. Köppen. M.. Simske. J.S.. Sims. P.A.. Firestein. B.L.. Hall. D.H.. Radice. A.D.. Rongo. C. and Hardin. J.D. (2001) Cooperative regulation of AJM-1 by Discs large and LET-413 controls junctional tightness of Caenorhabditis elegans epithelia. Nature Cell Biology. 3:983-991. |
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