Families of Protein Phosphatase 1 Modulators Activated by Protein Kinases A and C: Focus on Brain

Protein phosphatase 1 (PP1) regulation can contribute significantly to the modulation of key cellular processes, including transcription, protein translation, apoptosis, glycogen metabolism, muscle contraction, and cell division (1) PP1 regulation can also alter information processing in neurons by regulating the phosphorylation of proteins that include neurotransmitter receptors, voltage-gated ion channels, and ion pumps (2, 3). It is interesting to note that while there are roughly equal numbers of tyrosine kinases and phosphatases, the number of Ser/Thr kinases (∼400) far surpasses the number of Ser/Thr phosphatases (∼25), forming seemingly an asymmetric Ser/Thr kinase/phosphatase cycle (4). It is estimated that the PP1, PP2A, and PP2B phosphatases account for more than 90% of Ser/Thr dephosphorylation (5). Modulators of these phosphatases could thus play substantial regulatory roles. PP1 activities are regulated by two families of proteins that interact with PP1 and change its function in ways that depend on their phosphorylation/dephosphorylation by serine/threonine protein kinases and phosphatases (6). cAMP-dependent protein kinase (PKA) phosphorylates the PP1 inhibitors dopamine- and cAMP-regulated phosphoprotein (DARPP)-32 and inhibitor-1 (3, 7, 8). Protein kinase C (PKC) phosphorylates the PP1 inhibitors PKC-potentiated PP1 inhibitor (CPI)-17 (9), phosphatase holoenzyme inhibitor (PHI)-1 (10), kinase enhanced phosphatase inhibitor (KEPI) (11), and gut and brain phosphatase inhibitor (GBPI) (12). These two families of PKA- and PKC-dependent PP1 inhibitors are the major focus of this review. In addition, other families of PP1 inhibitors, such as TARPP and NIPP1, are phosphorylated by PKA (8, 13, 14), G-substrate by cGMP-dependent protein kinase (PKG) (15), and inhibitor-2 by glycogen synthase kinase-3 (GSK-3) (16). Phosphatases that terminate the activities of PP1 regulatory phosphoproteins (17) include protein phosphatase 2B (calcineurin), which dephosphorylates DARPP-32 and ends its ability to inhibit PP1 (18). Phosphorylation and dephosphorylation events can dramatically alter the abilities of several PP1 inhibitors to alter PP1 activities. PP1 inhibition is enhanced up to 1000-fold by phosphorylation of DARPP-32, inhibitor-1, G-substrate, CPI-17, PHI-1, KEPI, and GBPI (1, 7, 10-12, 19). In contrast, phosphorylation of NIPP1 and inhibitor-2 reduces their abilities to inhibit PP1 (13, 16). PP1 inhibitors are thus active cellular regulators that can alter patterns of cellular phosphorylation based on signals received through specific classes of G-protein-coupled and other cell surface receptors. Because of the exceptionally large number of PP1 substrates, cells have developed complex mechanisms in response of extracellular signals to target and regulate PP1 activities using more than 50 regulatory subunits (4) whose activities themselves are regulated by extracellular signals using receptors and kinases. While PP1 is conserved from prokaryotes to eukaryotes (20), PP1 regulatory subunits increase drastically in their sophistication and numbers from unicellular eukaryotes to multicellular organisms and mammals (6, 21). Small heat-stable PP1 inhibitory proteins regulated by PKA and PKC are evolutionarily new molecules that appear to have evolved in response to more demanding tasks of higher organisms that include learning (see later). G-protein-coupled and other receptors relate extracellular signals to PKA or PKC that activate these inhibitors to relieve PP1 suppression and alter neuronal activities. They serve complementary roles to kinase regulation in enhancing overall phosphorylation.