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The Journal of Neuroscience, October 15, 2008, 28(42):10460-10471; doi:10.1523/JNEUROSCI.2518-08.2008

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Cellular/Molecular
Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP/PKA Signaling in the Striatum

Akinori Nishi,^1,2,4 Mahomi Kuroiwa,¹ Diane B. Miller,³ James P. O'Callaghan,³ Helen S. Bateup,⁴ Takahide Shuto,¹ Naoki Sotogaku,¹ Takaichi Fukuda,⁶ Nathaniel Heintz,⁵ Paul Greengard,⁴ and Gretchen L. Snyder⁷

¹Department of Pharmacology, Kurume University School of Medicine and ²Japan Science of Technology Agency, Core Research for Evolutional Science and Technology, Kurume, Fukuoka 830-0011, Japan, ³Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, ⁴Laboratory of Molecular and Cellular Neuroscience and ⁵Laboratory of Molecular Biology, The Rockefeller University, New York, New York 10021, ⁶Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, and ⁷Intra-Cellular Therapies, Inc., New York, New York 10032

Correspondence should be addressed to Dr. Akinori Nishi, Department of Pharmacology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. Email: nishia{at}med.kurume-u.ac.jp

Phosphodiesterase (PDE) is a critical regulator of cAMP/protein kinase A (PKA) signaling in cells. Multiple PDEs with different substrate specificities and subcellular localization are expressed in neurons. Dopamine plays a central role in the regulation of motor and cognitive functions. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade, and therefore controlled by PDE activity. We used in vitro and in vivo biochemical techniques to dissect the roles of PDE4 and PDE10A in dopaminergic neurotransmission in mouse striatum by monitoring the ability of selective PDE inhibitors to regulate phosphorylation of presynaptic [e.g., tyrosine hydroxylase (TH)] and postsynaptic [e.g., dopamine- and cAMP-regulated phosphoprotein of M_r 32 kDa (DARPP-32)] PKA substrates. The PDE4 inhibitor, rolipram, induced a large increase in TH Ser40 phosphorylation at dopaminergic terminals that was associated with a commensurate increase in dopamine synthesis and turnover in striatum in vivo. Rolipram induced a small increase in DARPP-32 Thr34 phosphorylation preferentially in striatopallidal neurons by activating adenosine A_2A receptor signaling in striatum. In contrast, the PDE10A inhibitor, papaverine, had no effect on TH phosphorylation or dopamine turnover, but instead robustly increased DARPP-32 Thr34 and GluR1 Ser845 phosphorylation in striatal neurons. Inhibition of PDE10A by papaverine activated cAMP/PKA signaling in both striatonigral and striatopallidal neurons, resulting in potentiation of dopamine D₁ receptor signaling and inhibition of dopamine D₂ receptor signaling. These biochemical results are supported by immunohistochemical data demonstrating differential localization of PDE10A and PDE4 in striatum. These data underscore the importance of individual brain-enriched cyclic-nucleotide PDE isoforms as therapeutic targets for neuropsychiatric and neurodegenerative disorders affecting dopamine neurotransmission.

Key words: phosphodiesterase; DARPP-32; tyrosine hydroxylase; immunohistochemistry; rolipram; papaverine

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Received May 30, 2008; revised July 27, 2008; accepted Aug. 29, 2008.

Correspondence should be addressed to Dr. Akinori Nishi, Department of Pharmacology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. Email: nishia{at}med.kurume-u.ac.jp

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