Neurotransmission modulates a complex network of signaling pathways

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Role of Cdk5 in Neuronal Plasticity and Drug Abuse
Neurotransmission modulates a complex network of
signaling pathways Through this modulation,
neurotransmission affects functional and
structural plasticity which underlies learning
and memory. Dysregulation of these same pathways
underlies the long-term adaptive changes
associated with drug addiction. The neuronal
kinase, Cdk5, regulates a number of these
pathways.
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How might Cdk5 be involved in neuronal functional
plasticity?

• Cdk5 phosphorylates
• Voltage-gated Ca2 channels
• Dephosphins, amphiphysin I dynamin I
• MEK
• PSD-95
• NR2A subunit of the NMDA receptor
• Protein phosphatase inhibitor-1
• DARPP-32
• Cdk5 activators p35 and p39 interact with
• CaMKII in a Ca2 dependent manner

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Phosphorylation of inhibitor-1 by
proline-directed kinases
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Ser67 inhibitor-1 is phosphorylated by Cdk5 but
not MAPK in striatum
con
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Conditional Cdk5 Knockout Mice
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AAV-Cre mediated recombination in the NAcc
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Proteins Identified by Neuroproteomics as Targets
of Chronic Cocaine
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Identification of CDK5 Regulated Phosphoproteins
CDK5(-)
CDK5()
Silver Staining
pH 3
7 3
7 3
7
MW (kDa)
198-- 115-- 93-- 50-- 36--
29-- 21--
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2
2
4
4
1
1
1
5
3
3
5
3
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Tyrosine hydroxylase is phosphorylated by Cdk5 in
striatum
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CONCLUSIONS A complex network of signaling
pathways forms the basis of synaptic
plasticity Normal, as well as aberrant,
neurotransmission modulates neuronal circuitry
through these biochemical signaling
pathways Cdk5 has now been implicated to affect
many of these pathways, including regulation of
protein phosphatases Therefore, Cdk5 may mediate
both functional and structural plasticity and
influence learning and memory. In this manner,
Cdk5-dependent changes in neuroplasticity may
result in the formation of the addicted state.
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UT Southwestern David Benavides Yong
Pan Janice Kansy Michael Lloyd Bogachan
Sahin Chan Ngyuen Eric Nestler Ralph DiLione
Paul Greengard Gretchen Snyder Akinori
Nishi Angus Nairn Jane Taylor Allen
Fienberg Per Svenningsson
Paul Fitzpatrick Bruce Hope Laurent
Meijer Pierre Chambon Shirish
Shenolikar Li-Huei Tsai
Zhen Yan Andy Czernik Hugh Hemmings Charles
Ouimet Jingshan Chen Shinichi Hisanaga John
Haycock