PPP1R1B

Protein phosphatase 1, regulatory (inhibitor) subunit 1B
Identifiers
Symbols	PPP1R1B ; DARPP-32; DARPP32
External IDs	OMIM: 604399 MGI: 94860 HomoloGene: 12972 GeneCards: PPP1R1B Gene
EC number	3.1.3.16
Gene ontology Molecular function • protein kinase inhibitor activity • protein phosphatase inhibitor activity • protein serine/threonine phosphatase inhibitor activity • protein binding • protein phosphatase type 1 regulator activity • D1 dopamine receptor binding • D2 dopamine receptor binding • D3 dopamine receptor binding • D4 dopamine receptor binding • D5 dopamine receptor binding Cellular component • nucleus • cytoplasm • cytosol • neuronal cell body Biological process • response to amphetamine • transcription, DNA-templated • signal transduction • negative regulation of female receptivity • visual learning • intracellular signal transduction • negative regulation of catalytic activity • regulation of catalytic activity • negative regulation of cyclin-dependent protein kinase activity Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	84152	19049
Ensembl	ENSG00000131771	ENSMUSG00000061718
UniProt	Q9UD71	Q60829
RefSeq (mRNA)	NM_001242464	NM_144828
RefSeq (protein)	NP_001229393	NP_659077
Location (UCSC)	Chr 17: 39.63 – 39.64 Mb	Chr 11: 98.35 – 98.36 Mb
PubMed search

Protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), is a protein that in humans is encoded by the PPP1R1B gene.^[1][2]

Function

Midbrain dopaminergic neurons play a critical role in multiple brain functions, and abnormal signaling through dopaminergic pathways has been implicated in several major neurologic and psychiatric disorders. One well-studied target for the actions of dopamine is DARPP32. In the densely dopamine- and glutamate-innervated rat caudate-putamen, DARPP32 is expressed in medium-sized spiny neurons^[3] that also express dopamine D1 receptors.^[4] The function of DARPP32 seems to be regulated by receptor stimulation. Both dopaminergic and glutamatergic (NMDA) receptor stimulation regulate the extent of DARPP32 phosphorylation, but in opposite directions.^[5] Dopamine D1 receptor stimulation enhances cAMP formation, resulting in the phosphorylation of DARPP32;^[4] (this is disputed by more recent research that claims cAMP signaling induces dephosphorylation of DARPP32^[6]) phosphorylated DARPP32 is a potent protein phosphatase-1 (PPP1CA) inhibitor.^[7] NMDA receptor stimulation elevates intracellular calcium, which leads to activation of calcineurin and dephosphorylation of phospho-DARPP32, thereby reducing the phosphatase-1 inhibitory activity of DARPP32.^[1][5]

Clinical significance

This gene is also known as DARPP-32, highlighting its role as a dopamine- and cyclic AMP-regulated phosphoprotein. As such PPP1R1B affects dopamine,^[8] glutamate and adenosine; and there is some support for a role of the gene in schizophrenia, as well as being involved in the action of drugs including cocaine, amphetamine, nicotine, LSD, caffeine, PCP, ethanol and morphine,^[9] and in Parkinson's disease or EPS (Extra-pyramidal symptoms).^[10] DARPP-32 levels are decreased in the dorsolateral prefrontal cortex and lymphocytes of both schizophrenia and bipolar disorder patients.^[11][12][13] This alteration is suggested to be related to the pathology, since antipsychotics do not regulate the expression of DARPP-32.^[14][15]

A considerable proportion of the psychomotor effects of cannabinoids can be accounted for by a signaling cascade in striatal projection neurons involving PKA-dependent phosphorylation of DARPP-32, achieved via modulation of dopamine D2 and adenosine A2A transmission.^[16]

PPP1R1B has also been associated with improved transfer of information between the striatum and the prefrontal cortex, suggesting that variants of PPP1R1B can in some circumstances lead to improved and more flexible cognition, while, in the presence of other genetic and environmental factors, it may lead to symptoms of schizophrenia.^[17]

Regulation

Brain-derived neurotrophic factor regulates the expression of DARPP-32.^[18] The Akt and CDK5/p35 intracelular pathway is suggested to be involved on this regulation.^[19] Also, neuronal calcium sensor-1 was suggested to modulate the expression of DARPP-32.^[20]

Discovery

PPP1R1B was discovered by Paul Greengard and his co-workers.^[2]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|{{{bSize}}}px|alt=Nicotine Activity on Dopaminergic Neurons edit]]

Nicotine Activity on Dopaminergic Neurons edit

1. The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".

References

1. "Entrez Gene: PPP1R1B protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)".
2. Brené S, Lindefors N, Ehrlich M, Taubes T, Horiuchi A, Kopp J, Hall H, Sedvall G, Greengard P, Persson H (March 1994). "Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue". J. Neurosci. 14 (3 Pt 1): 985–98. PMID 8120638.
3. Ouimet CC, Greengard P (February 1990). "Distribution of DARPP-32 in the basal ganglia: an electron microscopic study". J. Neurocytol. 19 (1): 39–52. doi:10.1007/BF01188438. PMID 2191086.
4. Walaas SI, Greengard P (January 1984). "DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain". J. Neurosci. 4 (1): 84–98. PMID 6319627.
5. Halpain S, Girault JA, Greengard P (January 1990). "Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices". Nature 343 (6256): 369–72. doi:10.1038/343369a0. PMID 2153935.
6. Nishi, A.; Bibb, J. A.; Snyder, G. L.; Higashi, H.; Nairn, A. C.; Greengard, P. (2000-11-07). "Amplification of dopaminergic signaling by a positive feedback loop". Proceedings of the National Academy of Sciences of the United States of America 97 (23): 12840–12845. doi:10.1073/pnas.220410397. ISSN 0027-8424. PMC 18851. PMID 11050161.
7. Hemmings HC, Greengard P, Tung HY, Cohen P (1984). "DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1". Nature 310 (5977): 503–5. doi:10.1038/310503a0. PMID 6087160.
8. Scott L, Forssberg H, Aperia A, Diaz-Heijtz R (October 2005). "Locomotor effects of a D1R agonist are DARPP-32 dependent in adult but not weanling mice". Pediatr. Res. 58 (4): 779–83. doi:10.1203/01.PDR.0000180553.23507.31. PMID 16189209.
9. Svenningsson P, Nairn AC, Greengard P (2005). "DARPP-32 mediates the actions of multiple drugs of abuse". AAPS J 7 (2): E353–60. doi:10.1208/aapsj070235. PMC 2750972. PMID 16353915.
10. Clinton SM, Ibrahim HM, Frey KA, Davis KL, Haroutunian V, Meador-Woodruff JH (October 2005). "Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin". Am J Psychiatry 162 (10): 1859–71. doi:10.1176/appi.ajp.162.10.1859. PMID 16199832.
11. Albert KA, Hemmings HC Jr, Adamo AI, Potkin SG, Akbarian S, Sandman CA, Cotman CW, Bunney WE Jr, Greengard P (August 2002). "Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia". Arch Gen Psychiatry 59 (8): 705–12. doi:10.1001/archpsyc.59.8.705. PMID 12150646.
12. Ishikawa M, Mizukami K, Iwakiri M, Asada T (August 2007). "Immunohistochemical and immunoblot analysis of Dopamine and cyclic AMP-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32) in the prefrontal cortex of subjects with schizophrenia and bipolar disorder". Prog Neuropsychopharmacol Biol Psychiatry 31 (6): 1177–81. doi:10.1016/j.pnpbp.2007.04.013. PMID 17521792.
13. Torres KC, Souza BR, Miranda DM, Nicolato R, Neves FS, Barros AG, Dutra WO, Gollob KJ, Correa H, Romano-Silva MA (March 2009). "The leukocytes expressing DARPP-32 are reduced in patients with schizophrenia and bipolar disorder". Prog Neuropsychopharmacol Biol Psychiatry 33 (2): 214–9. doi:10.1016/j.pnpbp.2008.10.020. PMID 19059449.
14. Souza BR, Motta BS, Rosa DV, Torres KC, Castro AA, Comim CM, Sampaio AM, Lima FF, Jeromin A, Quevedo J, Romano-Silva MA (August 2008). "DARPP-32 and NCS-1 expression is not altered in brains of rats treated with typical or atypical antipsychotics". Neurochem Res 33 (3): 533–8. doi:10.1007/s11064-007-9470-2. PMID 17763944.
15. Souza BR, Torres KC, Miranda DM, Motta BS, Scotti-Muzzi E, Guimarães MM, Carneiro DS, Rosa DV, Souza RP, Reis HJ, Jeromin A, Romano-Silva MA (June 2010). "Lack of effects of typical and atypical antipsychotics in DARPP-32 and NCS-1 levels in PC12 cells overexpressing NCS-1". J Negat Results Biomed 9: 4. doi:10.1186/1477-5751-9-4. PMC 2912242. PMID 20565907.
16. Andersson M, Usiello A, Borgkvist A, Pozzi L, Dominguez C, Fienberg AA, Svenningsson P, Fredholm BB, Borrelli E, Greengard P, Fisone G (September 2005). "Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons". J. Neurosci. 25 (37): 8432–8. doi:10.1523/JNEUROSCI.1289-05.2005. PMID 16162925.
17. Meyer-Lindenberg A, Straub RE, Lipska BK, Verchinski BA, Goldberg T, Callicott JH, Egan MF, Huffaker SS, Mattay VS, Kolachana B, Kleinman JE, Weinberger DR (March 2007). "Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition". J. Clin. Invest. 117 (3): 672–82. doi:10.1172/JCI30413. PMC 1784004. PMID 17290303.
18. Stroppolo A, Guinea B, Tian C, Sommer J, Ehrlich ME (December 2001). "Role of phosphatidylinositide 3-kinase in brain-derived neurotrophic factor-induced DARPP-32 expression in medium size spiny neurons in vitro". J. Neurochem. 79 (5): 1027–32. doi:10.1046/j.1471-4159.2001.00651.x. PMID 11739615.
19. Bogush A, Pedrini S, Pelta-Heller J, Chan T, Yang Q, Mao Z, Sluzas E, Gieringer T, Ehrlich ME (March 2007). "AKT and CDK5/p35 mediate brain-derived neurotrophic factor induction of DARPP-32 in medium size spiny neurons in vitro.". J. Biol. Chem. 282 (10): 7352–9. doi:10.1074/jbc.M606508200. PMID 17209049.
20. Souza BR, Torres KC, Miranda DM, Motta BS, Caetano FS, Rosa DV, Souza RP, Giovani A Jr, Carneiro DS, Guimarães MM, Martins-Silva C, Reis HJ, Gomez MV, Jeromin A, Romano-Silva MA (2010). "Downregulation of the cAMP/PKA Pathway in PC12 Cells Overexpressing NCS-1". Cell. Mol. Neurobiol. 31 (1): 135–143. doi:10.1007/s10571-010-9562-4. PMID 20838877.

Further reading

• Hemmings HC, Nairn AC, Greengard P (December 1984). "DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated neuronal phosphoprotein. II. Comparison of the kinetics of phosphorylation of DARPP-32 and phosphatase inhibitor 1". J. Biol. Chem. 259 (23): 14491–7. PMID 6501303.
• Zachariou V, Sgambato-Faure V, Sasaki T, Svenningsson P, Berton O, Fienberg AA, Nairn AC, Greengard P, Nestler EJ (March 2006). "Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action". Neuropsychopharmacology 31 (3): 555–62. doi:10.1038/sj.npp.1300832. PMID 16123776.
• Rosack, J (20 September 2002). "DARPP-32 May Be Culprit in Schizophrenia Symptoms". Psychiatric News 37 (18): 24–24.

• Meister B, Askergren J, Tunevall G, et al. (1992). "Identification of a dopamine- and 3'5'-cyclic adenosine monophosphate-regulated phosphoprotein of 32 kD (DARPP-32) in parathyroid hormone-producing cells of the human parathyroid gland". J. Endocrinol. Invest. 14 (8): 655–61. doi:10.1007/bf03347888. PMID 1663529.
• Meister B, Schultzberg M, Hemmings HC, et al. (1992). "Dopamine- and adenosine-3',5'-monophosphate (cAMP)-regulated phosphoprotein of 32 kDa (DARPP-32) in the adrenal gland: immunohistochemical localization". J. Auton. Nerv. Syst. 36 (1): 75–84. doi:10.1016/0165-1838(91)90132-M. PMID 1721636.
• Meister B, Arvidsson U, Hemmings HC, et al. (1992). "Dopamine- and adenosine-3':5'-monophosphate (cAMP)-regulated phosphoprotein of Mr 32,000 (DARPP-32) in the retina of cat, monkey and human". Neurosci. Lett. 131 (1): 66–70. doi:10.1016/0304-3940(91)90338-T. PMID 1791981.
• Halpain S, Girault JA, Greengard P (1990). "Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices". Nature 343 (6256): 369–72. doi:10.1038/343369a0. PMID 2153935.
• Ouimet CC, Greengard P (1990). "Distribution of DARPP-32 in the basal ganglia: an electron microscopic study". J. Neurocytol. 19 (1): 39–52. doi:10.1007/BF01188438. PMID 2191086.
• Girault JA, Hemmings HC, Williams KR, et al. (1990). "Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II". J. Biol. Chem. 264 (36): 21748–59. PMID 2557337.
• Hemmings HC, Greengard P, Tung HY, Cohen P (1984). "DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1". Nature 310 (5977): 503–5. doi:10.1038/310503a0. PMID 6087160.
• Walaas SI, Greengard P (1984). "DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain". J. Neurosci. 4 (1): 84–98. PMID 6319627.
• Brené S, Lindefors N, Ehrlich M, et al. (1994). "Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue". J. Neurosci. 14 (3 Pt 1): 985–98. PMID 8120638.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Kwon YG, Huang HB, Desdouits F, et al. (1997). "Characterization of the interaction between DARPP-32 and protein phosphatase 1 (PP-1): DARPP-32 peptides antagonize the interaction of PP-1 with binding proteins". Proc. Natl. Acad. Sci. U.S.A. 94 (8): 3536–41. doi:10.1073/pnas.94.8.3536. PMC 20474. PMID 9108011.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Mayerhofer A, Hemmings HC, Snyder GL, et al. (1999). "Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro". J. Clin. Endocrinol. Metab. 84 (1): 257–64. doi:10.1210/jc.84.1.257. PMID 9920093.
• Bibb JA, Snyder GL, Nishi A, et al. (2000). "Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons". Nature 402 (6762): 669–71. doi:10.1038/45251. PMID 10604473.
• Mayerhofer A, Fritz S, Grünert R, et al. (2001). "D1-Receptor, DARPP-32, and PP-1 in the primate corpus luteum and luteinized granulosa cells: evidence for phosphorylation of DARPP-32 by dopamine and human chorionic gonadotropin". J. Clin. Endocrinol. Metab. 85 (12): 4750–7. doi:10.1210/jc.85.12.4750. PMID 11134138.
• El-Rifai W, Smith MF, Li G, et al. (2002). "Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP". Cancer Res. 62 (14): 4061–4. PMID 12124342.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Beckler A, Moskaluk CA, Zaika A, et al. (2003). "Overexpression of the 32-kilodalton dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein in common adenocarcinomas". Cancer 98 (7): 1547–51. doi:10.1002/cncr.11654. PMID 14508844.
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