Ž . Brain Research Reviews 26 1998 274–284 The DARPP-32rprotein phosphatase-1 cascade: a model for signal integration 1 Paul Greengard a , Angus C. Nairn a, ) , Jean-Antoine Girault b , Charles C. Ouimet c , Gretchen L. Snyder a , Gilberto Fisone d , Patrick B. Allen a , Allen Fienberg a , Akinori Nishi a a Laboratory of Molecular and Cellular Neuroscience, The Rockefeller UniÕersity, Box 296, 1230 York AÕenue, New York, NY 10021, USA b INSERM 114, 11 place Marcelin-Berthelot, 75231 Paris, Cedex 05, France c Department of Psychology, Florida State UniÕersity, Tallahassee, FL 32306, USA d Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden Contents 1. Introduction ........................................................................ 274 2. Anatomical distribution of DARPP-32 and PP-1..................................................... 274 3. Regulation of phosphorylation of DARPP-32 at threonine 34 .............................................. 275 4. Regulation of DARPP-32 via novel phosphorylation sites ................................................ 279 5. Structural basis for the interaction of DARPP-32 and PP-1 ............................................... 280 6. Regulation of physiological effectors by the DARPP-32rPP-1cascade ......................................... 281 7. A central role for DARPP-32 in the physiological regulation of medium spiny neurons of the neostriatum ...................... 282 Acknowledgements...................................................................... 283 References .......................................................................... 283 1. Introduction Studies of signal transduction carried out over the past decade have demonstrated a central role for the DARPP-32 Ž dopamine- and cAMP-regulated phosphoprotein, of ap- . Ž . parent M 32 000 rprotein phosphatase-1 PP-1 cascade r in integration of neurotransmitter pathways in medium spiny neurons of the neostriatum. Excitatory and inhibitory neurotransmitters have opposing actions on the state of phosphorylation of DARPP-32. DARPP-32, phosphory- Ž . lated by cAMP-dependent protein kinase PKA , acts as a ) Ž . Corresponding author. Fax: q1 212 327-7888; E-mail: nairn@rockvax.rockefeller.edu 1 Published on the World Wide Web on 22 January 1998. potent inhibitor of PP-1, one of the major serinerthreonine phosphatases in the central nervous system. By controlling the state of phosphorylation of a variety of downstream physiological effectors in a coordinated manner, the DARPP-32rPP-1 cascade regulates the functional state of neostriatal neurons. This review provides a brief summary of our recent studies of the DARPP-32rPP-1 cascade. 2. Anatomical distribution of DARPP-32 and PP-1 DARPP-32 is highly enriched in the caudatoputamen, w x Ž nucleus accumbens and olfactory tubercle 48,63 Fig. 1, brain regions that receive a dense dopamine input from the substantia nigra and ventral tegmental area. Over 95% of the neurons in the caudatoputamen are of the medium 0165-0173r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.