Many drugs of abuse target dopaminergic neurotransmission in the striatum. It is important to biochemically characterize intracellular signal transduction both in post-synaptic dopaminoceptive neurons of striatum and in pre-synaptic dopaminergic neurons of the midbrain in order to provide clearer information about how numerous, interacting signaling cascades are altered by drug addiction. Previously, we have shown that the neuronal protein kinase, Cdk5 (cyclin-dependent kinase-5), is an important regulator of dopaminergic neurotransmission. Furthermore, we have shown that Cdk5 and its neuron-specific activating cofactor, p35, are targets of chronic cocaine exposure. More recently, we have found that chronic cocaine-induced effects on neuronal synaptic morphology in the nucleus accumbens, the ventral portion of the striatum, which is particularly important for cocaine's behavioral effects, are under the control of Cdk5. We now propose to further characterize the role of Cdk5 in striatal brain function and determine its role in the processes that contribute to the addictive state. Toward this goal, we will investigate the ability of Cdk5 to regulate the activity of a striatal post-synaptic target (protein phosphatase inhibitor-1), and a pre-synaptic target tyrosine hydroxylase). In addition, we will search, using a proteomic approach, for additional proteins that mediate Cdk5-dependent processes in the striatum that contribute to cocaine action. The goal of this work is to identify new targets and therefore new biomolecular mechanisms underlying drug addiction. This information may also serve as the basis for the development of novel treatments for this disorder.
| Pozo, Karine; Bibb, James A (2016) The Emerging Role of Cdk5 in Cancer. Trends Cancer 2:606-618 |
| Bjorness, Theresa E; Dale, Nicholas; Mettlach, Gabriel et al. (2016) An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep. J Neurosci 36:3709-21 |
| Yousuf, Mohammad A; Tan, Chunfeng; Torres-Altoro, Melissa I et al. (2016) Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury. J Neurochem 138:317-27 |
| Plattner, Florian; Hayashi, Kanehiro; Hernández, Adan et al. (2015) The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci 18:1094-100 |
| Pozo, Karine; Hillmann, Antje; Augustyn, Alexander et al. (2015) Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis. Oncotarget 6:12080-93 |
| Tassin, Tara C; Benavides, David R; Plattner, Florian et al. (2015) Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain. J Biol Chem 290:16319-29 |
| Fan, Gaofeng; Aleem, Saadat; Yang, Ming et al. (2015) Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase. J Biol Chem 290:15934-47 |
| Plattner, Florian; Hernández, Adan; Kistler, Tara M et al. (2014) Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron 81:1070-1083 |
| Meyer, Douglas A; Torres-Altoro, Melissa I; Tan, Zhenjun et al. (2014) Ischemic stroke injury is mediated by aberrant Cdk5. J Neurosci 34:8259-67 |
| Pozo, Karine; Castro-Rivera, Emely; Tan, Chunfeng et al. (2013) The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24:499-511 |
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