# Presentation: 315881

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## Neurotransmission modulates a complex network of signaling pathways

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- 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.

**Role of Cdk5 in Neuronal Plasticity and Drug Abuse**

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## How might Cdk5 be involved in neuronal functional plasticity?

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**Cdk5 phosphorylates:****	**** **
**Voltage-gated Ca****2+**** 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 Ca****2+**** dependent manner **

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## Phosphorylation of inhibitor-1 by proline-directed kinases

## Ser67 inhibitor-1 is phosphorylated by Cdk5 but not MAPK in striatum

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## Conditional Cdk5 Knockout Mice

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**Conditional Cdk5 Knockout Mice**

## AAV-Cre mediated recombination in the NAcc

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## Proteins Identified by Neuroproteomics as Targets of Chronic Cocaine

**Proteins Identified by Neuroproteomics as Targets of Chronic Cocaine**

## pH   3                                                        7      3                                                            7         3                                                         7

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- pH   3                                                        7      3                                                            7         3                                                         7

- CDK5(-)

- CDK5(+)

- Silver Staining

- 198--
- 115--
-   93--
-   50--
-   36--
-   29--
-   21--

- MW
- (kDa)

**Identification of CDK5 Regulated Phosphoproteins**

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## Tyrosine hydroxylase is phosphorylated by Cdk5 in striatum

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## CONCLUSIONS

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- 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 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

- Paul Greengard
- Gretchen Snyder
- Akinori Nishi
- Angus Nairn
- Jane Taylor
- Allen Fienberg
- Per Svenningsson