Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Takahashi, Satoru; Ohshima, Toshio; Cho, Andrew; Sreenath, Taduru; Iadarola, Michael J.; Pant, Harish C.; Kim, Yong; Nairn, Angus C.; Brady, Roscoe O.; Greengard, Paul; Kulkarni, Ashok B.

doi:10.1073/pnas.0409456102

Cited by 79 publications

(69 citation statements)

References 27 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, only suppression of p35 by antisense oligonucleotide treatment but not of the highly related isoform p39 selectively reduces cdk5 activity (24). In addition, levels of p35 but not of cdk5 protein are rate-limiting for cdk5 activity (25). In concordance, we assessed the influence of Hsp90 inhibition on p35 cellular expression.…”

Section: Inhibition Of Hsp90 Reduces Cellular Levels Of Both P35 and supporting

confidence: 57%

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Luo

Dou

Rodina

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

253

226

View full text Add to dashboard Cite

Neurodegeneration, a result of multiple dysregulatory events, is a lengthy multistep process manifested by accrual of mutant variants and abnormal expression, posttranslational modification, and processing of certain proteins. Accumulation of these dysregulated processes requires a mechanism that maintains their functional stability and allows the evolution of the neurodegenerative phenotype. In malignant cells, the capacity to buffer transformation has been attributed to heat-shock protein 90 (Hsp90). Although normal proteins seem to require limited assistance from the chaperone, their aberrant counterparts seem to be highly dependent on Hsp90. Whereas enhanced Hsp90 affinity for mutated or functionally deregulated client proteins has been observed for several oncoproteins, it is unknown whether Hsp90 plays a similar role for neuronal proteins and thus maintains and facilitates the transformed phenotype in neurodegenerative diseases. Tauopathies are neurodegenerative diseases characterized by aberrant phosphorylation and/or expression of Tau protein, leading to a timedependent accumulation of Tau aggregates and subsequent neuronal death. Here, we show that the stability of p35, a neuronal protein that activates cyclin-dependent protein kinase 5 through complex formation leading to aberrant Tau phosphorylation, and that of mutant but not WT Tau protein is maintained in tauopathies by Hsp90. Inhibition of Hsp90 in cellular and mouse models of tauopathies leads to a reduction of the pathogenic activity of these proteins and results in elimination of aggregated Tau. The results identify important roles played by Hsp90 in maintaining and facilitating the degenerative phenotype in these diseases and provide a common principle governing cancer and neurodegenerative diseases.cyclin-dependent protein kinase 5 ͉ neurodegeneration ͉ Tau

show abstract

Section: Inhibition Of Hsp90 Reduces Cellular Levels Of Both P35 and supporting

confidence: 57%

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Luo

Dou

Rodina

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

253

226

View full text Add to dashboard Cite

show abstract

“…Six-to 8-week-old male p35 Ϫ/Ϫ or Tgp35 mice (8,32) were used for these studies. Age-matched male C57BL6͞129SVJ and FVBN WT mice (The Jackson Laboratory) served as controls for p35 Ϫ/Ϫ and Tgp35 mice, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The elevated Cdk5 activity was consistent with the formation of p25 protein. This elevated Cdk5 activity could be caused by increased levels of p35 and͞or p25, because Tgp35 mice or transgenic mice overexpressing p25 also have increased Cdk5 activity (8,31).…”

Section: Figmentioning

confidence: 99%

“…Because Cdk5 activity was increased as a result of inflammation (Fig. 4), we analyzed nociceptive behavior in p35 Ϫ/Ϫ mice, which have significantly reduced Cdk5 activity caused by the lack of p35 (32), and Tgp35 mice, which exhibit Cdk5 hyperactivity because of p35 overexpression (8). We tested the basal thermal nociceptive responses in these mice by using the Hargreaves test (HT) (Fig.…”

Section: Altered Nociceptive Response In P35 ؊/؊ and Tgp35 Mice To Basalmentioning

confidence: 99%

“…Transcriptional and translational regulation of p35 and p39 plays a key role in the maintenance of normal Cdk5 activity. We and others have previously reported critical roles for Cdk5 and its activators in the development of the mammalian nervous system (6)(7)(8)(9). Emerging evidence of Cdk5's involvement in several neuronal functions, such as neuronal migration, neurotransmitter release, neuronal plasticity, memory, learning, addiction, and apoptosis, has established Cdk5 as a potential master regulator of many vital neuronal functions (10).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Cyclin-dependent kinase 5 activity regulates pain signaling

Pareek

Keller

Kesavapany

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

107

151

View full text Add to dashboard Cite

Several molecules and cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine͞threonine kinase implicated in the development and disease of the mammalian nervous system. The precise role of this kinase in sensory pathways has not been well characterized. Here we report a molecular role for Cdk5 in nociception. We identified the expression of Cdk5 and its activator p35 in nociceptive neurons, which is modulated during a peripheral inflammatory response. Increased calpain activity in sensory neurons after inflammation resulted in the cleavage of p35 to p25, which forms a more stable complex with Cdk5 and, consequently, leads to elevation of Cdk5 activity. p35 knockout mice (p35 ؊/؊ ), which exhibit significantly decreased Cdk5 activity, showed delayed responses to painful thermal stimulation compared with WT controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, were more sensitive to painful thermal stimuli than were controls. In conclusion, our data demonstrate a role for Cdk5͞p35 activity in primary afferent nociceptive signaling, suggesting that Cdk5͞p35 may be a target for the development of analgesic drugs.nociception ͉ inflammation ͉ dorsal root ganglia ͉ trigeminal ganglia ͉ spinal cord P ain is a combination of sensory (discriminative) and affective (emotional) components. The sensory component of pain is defined as nociception and is required for survival and the maintenance of the integrity of the organism. However, sustained or chronic pain, particularly in humans, can result in secondary symptoms such as anxiety, depression, and a marked decrease in the quality of life (1, 2). Specific cell types and several molecules have been identified that detect and regulate nociceptive activity. Additionally, the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain have been elucidated, but the underlying molecular mechanisms remain unclear. So far, studies using genetically modified mice, antisense knockdowns in cells, gene expression assays (including DNA microarray-based expression profiling), and linkage mapping have identified several genes the expression levels of which are directly or indirectly affected during pain sensation and͞or that are involved in modulating pain (3). As a result, the number of proteins encoded by these genes continues to expand, and further investigation of their participation in pain pathways is required.Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (which belong to a family of small proline-directed serine͞threonine kinases), is mainly active in postmitotic neurons because of the selective neuronal expression of its activators, p35 and p39 (4, 5). Transcriptional and translational regulation of p35 and p39 plays a key role in the maintenance of normal Cdk5 activity. We and others have previously reported critical role...

show abstract

Protocols for Characterization of Cdk5 Kinase Activity

et al. 2021

Self Cite

View full text Add to dashboard Cite

Cyclin-dependent kinases (Cdks) are generally known to be involved in controlling the cell cycle, but Cdk5 is a unique member of this protein family for being most active in post-mitotic neurons. Cdk5 is developmentally important in regulating neuronal migration, neurite outgrowth, and axon guidance. Cdk5 is enriched in synaptic membranes and is known to modulate synaptic activity. Postnatally, Cdk5 can also affect neuronal processes such as dopaminergic signaling and pain sensitivity. Dysregulated Cdk5, in contrast, has been linked to neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Despite primarily being implicated in neuronal development and activity, Cdk5 has lately been linked to non-neuronal functions including cancer cell growth, immune responses, and diabetes. Since Cdk5 activity is tightly regulated, a method for measuring its kinase activity is needed to fully understand the precise role of Cdk5 in developmental and disease processes. This article includes methods for detecting Cdk5 kinase activity in cultured cells or tissues, identifying new substrates, and screening for new kinase inhibitors. Furthermore, since Cdk5 shares homology and substrate specificity with Cdk1 and Cdk2, the Cdk5 kinase assay can be used, with modification, to measure the activity of other Cdks as well.

show abstract

Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Cited by 79 publications

References 27 publications

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

Cyclin-dependent kinase 5 activity regulates pain signaling

Protocols for Characterization of Cdk5 Kinase Activity

Contact Info

Product

Resources

About