The sliver of brain called striatum plays a key role in integrating dopaminergic inputs from the midbrain and glutamatergic inputs from the thalamus and neocortex, a job that enables a person to process motor- and reward-related behaviors properly. Malfunction of the striatum results in the loss of dopaminergic neurons and an imbalance in neurotransmission—hallmarks of Parkinson’s disease (PD), drug addiction, and schizophrenia. Cyclin-dependent kinase 5 (CDK5) is a protein that regulates postsynaptic dopamine signaling by phosphorylating the postsynaptic protein DARPP-32, and subsequently inhibiting protein kinase A (PKA). When it comes to neurodegeneration, CDK5 is better known for its suspected role in Alzheimer’s disease, but recently has been implicated in a mouse model of Parkinson’s, as well (Smith et al., 2003). In the February 9 PNAS, Karima Chergui and Per Svenningsson, working with Paul Greengard at The Rockefeller University, New York, characterize the role of CDK5 in regulating presynaptic dopaminergic and glutamatergic transmission in the striatum. They propose that CDK5 inhibitors be developed as a novel treatment for disorders characterized by dopamine deficiency.

In the past, studies about CDK5’s role in neurodegeneration concentrated mostly on Alzheimer’s disease and stroke (for example, see ARF related news story, ARF CDK story, ARF Orlando CDK story, ARF calpain story; Liu et al., 2004; Smith et al., 2004). This work made attractive the idea of using a selective CDK5 inhibitor that competes with ATP binding on the kinase. Indirubins are one such new class of inhibitors that are derived from an active ingredient in traditional Chinese medicine (Polychronopoulos et al.). However, CDK5 inhibition could be harmful, too. Just last month, Li-Huei Tsai’s lab reported that CDK5 inhibition blocks LTP induction and NMDA-evoked currents in the hippocampus. Apparently, CDK5 phosphorylates the postsynaptic density protein 95 (PSD-95), and the resulting clustering of NMDA receptors might help determine the efficacy of synaptic transmission (Morabito et al., 2004).

Focusing their attention on the interplay between dopamine and glutamate in the striatum, Chergui and Svenningsson first used in situ hybridization to determine the distribution of CDK5 mRNA in the substantia nigra and neocortex, two main striatal inputs that might modulate dopamine release. Then, electrophysiology experiments in mouse brain slices revealed that, like cocaine, the CDK5 inhibitor roscovitine increased evoked dopamine release in nigrostriatal fibers. In fact, roscovitine augmented the effects of cocaine. This suggested to the authors that the effect of CDK5 inhibitors might be both presynaptic and postsynaptic. Looking to the striatal projection neurons and the neocortex, the researchers measured NMDA and AMPA excitatory postsynaptic currents (EPSC) in brain slices in which glutamatergic fibers were excited. When they added roscovitine or butyrolactone I (another CDK5 inhibitor) to the solution, they observed increased NMDA-EPSC amplitude and no effect on the AMPA-EPSC, leading them to conclude that CDK5 regulates the striatal release of dopamine but not glutamate.

Seeing that phosphorylation levels increased after incubating brain slices with CDK5 inhibitor, the researchers then examined the regulation of phosphorylation of key proteins. They infused mouse brain slices with roscovitine and amphetamine, a dopamine re-uptake inhibitor, and then observed increased phosphorylation of the NMDA receptor subunit NR1, and DARPP-32, a postsynaptic protein enriched in the striatum. They were able to weaken this effect with a D1 receptor antagonist, by damaging dopaminergic innervation, or by knocking out the D1 receptor, and these results convinced the authors that the CDK5 inhibitors exert a presynaptic action. In an effort to separate the presynaptic and postsynaptic actions, the researchers mutated the CDK5 site of DARPP-32, a change that handicapped roscovitine’s ability to increase phosphorylation of NR1 and DARPP-32. What’s more, addition of a D1 receptor antagonist potentiated this effect. This reduction in DARPP-32 phosphorylation indicated a postsynaptic action of CDK5, while the compounding effect caused by the D1 antagonist indicated a presynaptic regulation of dopamine release, according to the authors.

The researchers conclude that CDK5 regulates dopamine release, and that its activation of dopamine D1 receptors indirectly modulates the function of NMDA receptors. Furthermore, they say that this latter presynaptic action cooperates with a postsynaptic mechanism involving DARPP-32 to modulate glutamatergic transmission in the striatum.—Erene Mina.

Reference:
Chergui K, Svenningsson P, Greengard P Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. Proc Natl Acad Sci U S A. 2004 Feb 9 [Epub ahead of print] Abstract

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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.

References

News Citations

  1. Tau Kinase Mediates Stroke Damage
  2. Aiding and Abetting, Hyperactive CDK5 Gives Mouse Tangles
  3. Orlando: It’s Getting Hot around CDK5, Has the Field Noticed Yet?
  4. The Calpain Connection

Paper Citations

  1. . Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13650-5. PubMed.
  2. . Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression. J Neurochem. 2004 Feb;88(3):554-63. PubMed.
  3. . Emerging pathogenic role for cyclin dependent kinases in neurodegeneration. Cell Cycle. 2004 Mar;3(3):289-91. PubMed.
  4. . Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J Neurosci. 2004 Jan 28;24(4):865-76. PubMed.
  5. . 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.

Further Reading

Papers

  1. . 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.

Primary Papers

  1. . 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.