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Regulation of protein phosphatase-1 in neuronal signaling
-일시: 2001년 5월 16일(수) 오전 9:30-
-장소: 화학관 408호 멀티미디어 강의실
-연사: Professor Angus A. Nairn (Rockefeller University)
-연락처: 생명과 류성호 교수 (279-2292)
Protein phosphatase-1 (PP1) is a major eukaryotic protein serine/threonine phosphatase that regulates diverse cellular processes such as cell cycle progression, protein synthesis, transcription and neuronal signaling. A large amount of work has indicated that PP1 plays an important role in dopamine signaling in the central nervous system. PP1 is regulated by various protein inhibitors, including, inhibitor-1, its homolog DARPP-32, and inhibitor-2. PP1 is also regulated by its interaction with proteins that act in a manner distinct from the inhibitor proteins, by targeting the catalytic subunit to specific subcellular compartments and influencing substrate
We have characterized the interaction of PP1 with the inhibitor proteins, DARPP-32 and inhibitor-2, and the targeting subunits, spinophilin, neurabin and PNUTS. The neuronal PP1 targeting protein, spinophilin, appears to function by directing the PP1 catalytic subunit to synaptic spines in neurons and to regulate its activity toward physiological substrates. Characterization of the interactions between DARPP-32 and spinophilin with PP1 has facilitated the design of peptide antagonists capable of disrupting the regulation of AMPA type glutamate channels in neostriatal neurons. Recent studies have also revealed that DARPP-32 is phosphorylated by the cyclin-dependent kinase family member, cdk5. Phosphorylation by influences dopamine signaling by attenuating the ability of DARPP-32 to inhibit PP1. Furthermore, these studies indicate that the phosphorylation of DARPP-32 by cdk5 may play a role in the adaptive responses of the dopaminergic system to psychoactive drugs such as cocaine.
The disruption of normal dopaminergic neurotransmission is known to underlie certain neurological diseases, including Huntington's and Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. The biochemical characterization of DARPP-32 and the processes by which PP1 is regulated provides a rational new approach to developing drugs that may correct dopaminergic neurotransmission in these diseases. Some of our recent studies of DARPP-32 and PP1 will be reviewed in this lecture.