Signal transduction mechanisms must be considered not as linear processes initiated when first messengers bind to their receptors, but in the context of an intracellular fabric where signaling pathways intertwine and impinge upon each other in an extremely complex organization. Understanding this organization at the biochemical level is a key to understanding how neurons in the brain function as well as the basis of a variety of neurological disorders. The focus of my laboratory is the study of novel protein phosphorylation/dephosphorylation signaling events as they relate to normal cell function and disease. This work seeks to biochemically characterize novel signaling events and determine the physiological function of these events at the levels of individual cells, tissue and the whole organism.
A question of particular interest is the relationship between neurotransmission and neural outgrowth. We hypothesize that these two phenomena are related by counter-regulatory signaling mechanisms. One target of such regulatory mechanisms is the neuronal protein kinase, Cdk5. We are interested in identifying novel targets of Cdk5 which regulate both neurotransmission and neurite growth. The laboratory has a number of other areas of interest including drug abuse, neurodegenerative diseases, and novel drug discovery.
Methodological approaches in the laboratory center around protein biochemistry and neuropharmacology. A variety of molecular biological methods are used to generate purified proteins and reagents to characterize phosphorylation/dephosphorylation events in vitro. Physical biochemistry techniques including phosphopeptide mapping, phosphoamino acid analysis, HPLC, and mass spectrometry are used to identify novel sites of phosphorylation. Phosphorylation state-specific antibodies are then generated to study the signaling event of interest in vivo using acutely prepared brain slices or whole animals. Additionally, behavioral analysis, confocal microscopy an electrophysiological approaches may often be incorporated.
RECENT PUBLICATIONS
Saito T., Onuki R., Fujita Y., Kusakawa G., Ishiguro K., Bibb J.A., Kishimoto T., Hisanaga S., "Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation" J. Neurosci., 23:1189-97, 2003
Norholm, S., Bibb, J.A., Ouimet, C.C., Nestler, E.J., Taylor, J.R., and P. Greengard,P., "Cocaine-induced changes in striatal dendritic mophology are dependent on Cdk5 activity" Neuroscience, 116:19-22, 2003
Lindskog, M., Pozzi, L., Svenningsson, P., Fienberg, A., Bibb, J.A., Fredholm, B.B., Greengard, P., and G. Fisone, "The stimulant action of caffeine is mediated by an increase in the state of phosphorylation at the Cdk5 site of DARPP-32" Nature, 428:774-748, 2002
Yan, Z., Chi, P., Bibb, J.A., Ryan, T.A., and P. Greengard, "Roscovitine: A Novel Regulator of P/Q-type Calcium Channels" J. Physiol., 540:761-70, 2002
Nishi, A., Bibb, J.A., Matsuyama, S., Hamada, M., Higashi, H., Nairn, A.C. and Greengard, P., "Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-stes by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A" J. Neurochem., In press. 2003
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