. Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2191-6. PubMed.

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  1. The cyclin dependent kinases (CDKs) constitute a family of enzymes that regulates a variety of cellular functions. The importance of CDKs in cell cycle control has made these kinases attractive targets for the treatment of cancer (Sausville EA, Curr Med Chem Anti-Canc Agents 3: 47, 2003). Additional biological functions of CDKs continue to be discovered; for example, CDKs are required for the replication of some viruses and, hence, CDK inhibitors are generating interest as antiviral agents (Schang, 2002). CDK5 is unusual among the CDKs in that it is constitutively expressed primarily in neurons, where it is involved in cellular processes such as the phosphorylation of cytoskeletal proteins, the developmental migration of neurons, and neurite outgrowth. Because CDK5 phosphorylates specific sites on tau (the microtubule binding protein that, in a hyperphosphorylated state, comprises neurofibrillary tangles), its inhibition is a potential strategy for the treatment of Alzheimer’s disease and other tauopathies (Lau et al., 2002).

    Chergui, Svenningsson, and Greengard have identified an important new role for CDK5 as a modulator of dopaminergic and glutamatergic transmission in the striatum. Their findings indicate that, in addition to its negative regulatory effect on postsynaptic dopaminergic signaling, CDK5 packs a double wallop by negatively controlling the release of dopamine from the synaptic bouton, thereby also influencing glutamatergic transmission. The results have exciting implications for understanding the interplay of neuronal systems in the striatum, and offer promise for the development of new treatments for disorders in which these systems are dysfunctional, such as Parkinson’s disease. Realizing this promise may require some patience. Because of the high homology among CDKs, and the phylogenetic proximity of CDKs to other kinases such as extracellular signal-regulated kinases (ERKs) and glycogen synthase kinase 3 (GSK3), developing a highly selective CDK5 inhibitor will be a daunting task. Roscovitine, butyrolactone-I and olomoucine, for example, are potent inhibitors of (at least) CDKs 1 and 2, in addition to CDK5. However, the findings of Chergui and colleagues are a welcome addition to the growing evidence that CDK5 plays an important role in normal brain function as well as in diverse disease states. A safe, selective, and brain-penetrant CDK5 inhibitor could become a valuable addition to the pharmaceutical arsenal for treating several debilitating brain disorders.

    References:

    . Cyclin-dependent kinases as cellular targets for antiviral drugs. J Antimicrob Chemother. 2002 Dec;50(6):779-92. PubMed.

    . Cdk5 as a drug target for the treatment of Alzheimer's disease. J Mol Neurosci. 2002 Dec;19(3):267-73. PubMed.

    View all comments by Lary Walker

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  1. A Growing Portfolio: CDK5 Implicated in Parkinson’s, Too