Abstract
DARPP-32 (PPP1R1B) was discovered as a substrate of cAMP-dependent protein kinase (PKA) enriched in dopamine-innervated brain areas. It is one of three related, PKA-regulated inhibitors of protein phosphatase-1 (PP1). These inhibitors seem to have appeared in early vertebrate ancestors, possibly Gnathostomes. DARPP-32 has additional important biochemical properties including inhibition of PKA when phosphorylated by Cdk5 and regulation by casein kinases 1 and 2. It is highly enriched in specific neuronal populations, especially striatal medium-size spiny neurons. As PP1 inhibitor DARPP-32 amplifies and/or mediates many actions of PKA at the plasma membrane and in the cytoplasm, with a broad spectrum of potential targets and functions. DARPP-32 also undergoes a continuous and tightly regulated cytonuclear shuttling. This trafficking is controlled by phosphorylation of Ser-97, which is necessary for nuclear export. When phosphorylated on Thr-34 and dephosphorylated on Ser-97, DARPP-32 can inhibit PP1 in the nucleus and modulate signaling pathways involved in the regulation of chromatin response. Recent work with multiple transgenic and knockout mutant mice has allowed the dissection of DARPP-32 function in striato-nigral and striato-pallidal neurons. It is implicated in the action of therapeutic and abused psychoactive drugs, in prefrontal cortex function, and in sexual behavior. However, the contribution of DARPP-32 in human behavior remains poorly understood. Post-mortem studies in humans suggest possible alterations of DARPP-32 levels in schizophrenia and bipolar disorder. Genetic studies have revealed a polymorphism with possible association with psychological and psychopathological traits. In addition, a short isoform of DARPP-32, t-DARPP, plays a role in cancer, indicating additional signaling properties. Thus, DARPP-32 is a non-essential but tightly regulated signaling hub molecule which may improve the general performance of the neuronal circuits in which it is expressed.
Highlights
What we know today about signal transduction derives from early studies of the glycogen metabolism. Sutherland (1972) identified cAMP as the intracellular second messenger which mediates the action of glucagon and epinephrine on glycogen degradation through activation of glycogen phosphorylase
DARPP-32 is known as phospho-protein phosphatase-1 regulatory subunit 1B (PPP1R1B), its properties are not restricted to PP1 inhibition
DARPP-32 is one of several protein kinase (PKA)-regulated inhibitors of PP1 and has additional functions which endow it with a large number of possible regulatory roles
Summary
DARPP-32 has additional important biochemical properties including inhibition of PKA when phosphorylated by Cdk and regulation by casein kinases 1 and 2 It is highly enriched in specific neuronal populations, especially striatal medium-size spiny neurons. To better characterize the mode of action of neurotransmitters in various brain regions, Walaas et al (1983b) undertook a systematic regional study of proteins phosphorylated by second messengers-activated protein kinases Some of these substrates, or “third messengers” were evenly distributed whereas others were highly enriched in specific brain regions. Walaas observed the enrichment of a 32-kDa soluble PKA substrate in striatal slices extracts The phosphorylation of this protein highly expressed in DA-innervated brain regions, was regulated by DA and cAMP and it was termed DARPP-32 (dopamine and cAMP-regulated phospho-protein Mr 32,000; Walaas et al, 1983a). Not all of these cells express adenylyl-cyclase-coupled DA receptors (D1R and D5R) and DARPP-32 phosphorylation on Frontiers in Behavioral Neuroscience www.frontiersin.org
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