PPP1R1B

Last updated
PPP1R1B
Identifiers
Aliases PPP1R1B , DARPP-32, DARPP32, protein phosphatase 1 regulatory inhibitor subunit 1B
External IDs OMIM: 604399; MGI: 94860; HomoloGene: 12972; GeneCards: PPP1R1B; OMA:PPP1R1B - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001242464
NM_032192
NM_181505

NM_144828
NM_001313970

RefSeq (protein)

NP_001229393
NP_115568
NP_852606
NP_115568.2

NP_001300899
NP_659077

Location (UCSC) Chr 17: 39.63 – 39.64 Mb Chr 11: 98.24 – 98.25 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6]

Contents

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 [7] that also express dopamine D1 receptors. [8] 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. [9] Dopamine D1 receptor stimulation enhances cAMP formation, resulting in the phosphorylation of DARPP32; [8] (this is disputed by more recent research that claims cAMP signaling induces dephosphorylation of DARPP32 [10] ) phosphorylated DARPP32 is a potent protein phosphatase-1 (PPP1CA) inhibitor. [11] 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. [5] [9] DARPP-32 is critical for dopamine dependent striatal synaptic plasticity, [12] possibly by serving as a dopamine-dependent gating mechanism for calcium/CaMKII signaling. [13] It has been predicted that DARPP-32, in conjunction with ARPP-21, could also be involved in setting-up of eligibility trace-like temporal window for striatal postsynaptic signaling. [13]

Clinical significance

CNS

This gene is also known as DARPP-32, highlighting its role as a dopamine- and cyclic AMP-regulated phosphoprotein. As such PPP1R1B affects dopamine, [14] 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, [15] and in Parkinson's disease or EPS (Extra-pyramidal symptoms). [16] DARPP-32 levels are decreased in the dorsolateral prefrontal cortex and lymphocytes of both schizophrenia and bipolar disorder patients. [17] [18] [19] This alteration is suggested to be related to the pathology, since antipsychotics do not regulate the expression of DARPP-32. [20] [21]

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. [22]

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. [23]

Cancer

There are two protein products encoded by PPP1R1B: DARPP-32 and t-Darpp. t-Darpp is a truncated version of DARPP-32 as it is missing the first 36 amino acids at the N-terminus. [24] Both isoforms are overexpressed in a number of cancers including those derived from gastric, colon, prostate, esophageal, breast, and lung tissues. [25] [26] In Her-2-positive breast cancer cells, t-Darpp overexpression imparts resistance to Trastuzumab (Herceptin), the chemotherapy drug that shuts down the Her-2 signaling pathway. [27] [28] [29]

Regulation

Brain-derived neurotrophic factor regulates the expression of DARPP-32. [30] The Akt and CDK5/p35 intracellular pathway is suggested to be involved on this regulation. [31] Also, neuronal calcium sensor-1 was suggested to modulate the expression of DARPP-32. [32]

Discovery

PPP1R1B was discovered by Paul Greengard and his co-workers. [6]

Interactive pathway map

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

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|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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000131771 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000061718 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: PPP1R1B protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)".
  6. 1 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". The Journal of Neuroscience. 14 (3 Pt 1): 985–98. doi:10.1523/JNEUROSCI.14-03-00985.1994. PMC   6577526 . PMID   8120638.
  7. Ouimet CC, Greengard P (February 1990). "Distribution of DARPP-32 in the basal ganglia: an electron microscopic study". Journal of Neurocytology. 19 (1): 39–52. doi:10.1007/BF01188438. PMID   2191086. S2CID   33812522.
  8. 1 2 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". The Journal of Neuroscience. 4 (1): 84–98. doi:10.1523/JNEUROSCI.04-01-00084.1984. PMC   6564747 . PMID   6319627.
  9. 1 2 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. Bibcode:1990Natur.343..369H. doi:10.1038/343369a0. PMID   2153935. S2CID   4319592.
  10. Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P (November 2000). "Amplification of dopaminergic signaling by a positive feedback loop". Proceedings of the National Academy of Sciences of the United States of America. 97 (23): 12840–5. Bibcode:2000PNAS...9712840N. doi: 10.1073/pnas.220410397 . PMC   18851 . PMID   11050161.
  11. 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. Bibcode:1984Natur.310..503H. doi:10.1038/310503a0. PMID   6087160. S2CID   4307053.
  12. Yagishita S, Hayashi-Takagi A, Ellis-Davies GC, Urakubo H, Ishii S, Kasai H (September 2014). "A critical time window for dopamine actions on the structural plasticity of dendritic spines". Science. 345 (6204): 1616–20. Bibcode:2014Sci...345.1616Y. doi:10.1126/science.1255514. PMC   4225776 . PMID   25258080.
  13. 1 2 Nair AG, Bhalla US, Hellgren Kotaleski J (September 2016). "Role of DARPP-32 and ARPP-21 in the Emergence of Temporal Constraints on Striatal Calcium and Dopamine Integration". PLOS Computational Biology. 12 (9): e1005080. Bibcode:2016PLSCB..12E5080N. doi: 10.1371/journal.pcbi.1005080 . PMC   5008828 . PMID   27584878.
  14. 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". Pediatric Research. 58 (4): 779–83. doi: 10.1203/01.PDR.0000180553.23507.31 . PMID   16189209.
  15. Svenningsson P, Nairn AC, Greengard P (October 2005). "DARPP-32 mediates the actions of multiple drugs of abuse". The AAPS Journal. 7 (2): E353-60. doi:10.1208/aapsj070235. PMC   2750972 . PMID   16353915.
  16. 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". The American Journal of Psychiatry. 162 (10): 1859–71. doi:10.1176/appi.ajp.162.10.1859. PMID   16199832.
  17. Albert KA, Hemmings HC, Adamo AI, Potkin SG, Akbarian S, Sandman CA, Cotman CW, Bunney WE, Greengard P (August 2002). "Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia". Archives of General Psychiatry. 59 (8): 705–12. doi:10.1001/archpsyc.59.8.705. PMID   12150646. S2CID   1672878.
  18. 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". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 31 (6): 1177–81. doi:10.1016/j.pnpbp.2007.04.013. PMID   17521792. S2CID   27481326.
  19. 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". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 33 (2): 214–9. doi:10.1016/j.pnpbp.2008.10.020. PMID   19059449. S2CID   8431767.
  20. Souza BR, Motta BS, Rosa DV, Torres KC, Castro AA, Comim CM, Sampaio AM, Lima FF, Jeromin A, Quevedo J, Romano-Silva MA (March 2008). "DARPP-32 and NCS-1 expression is not altered in brains of rats treated with typical or atypical antipsychotics". Neurochemical Research. 33 (3): 533–8. doi:10.1007/s11064-007-9470-2. PMID   17763944. S2CID   27727055.
  21. 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". Journal of Negative Results in Biomedicine. 9: 4. doi: 10.1186/1477-5751-9-4 . PMC   2912242 . PMID   20565907.
  22. 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". The Journal of Neuroscience. 25 (37): 8432–8. doi:10.1523/JNEUROSCI.1289-05.2005. PMC   6725667 . PMID   16162925.
  23. 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". The Journal of Clinical Investigation. 117 (3): 672–82. doi:10.1172/JCI30413. PMC   1784004 . PMID   17290303.
  24. El-Rifai W, Smith MF, Li G, Beckler A, Carl VS, Montgomery E, Knuutila S, Moskaluk CA, Frierson HF, Powell SM (July 2002). "Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP". Cancer Research. 62 (14): 4061–4. PMID   12124342.
  25. Belkhiri A, Zhu S, El-Rifai W (April 2016). "DARPP-32: from neurotransmission to cancer". Oncotarget. 7 (14): 17631–40. doi:10.18632/oncotarget.7268. PMC   4951238 . PMID   26872373.
  26. Alam SK, Astone M, Liu P, Hall SR, Coyle AM, Dankert EN, Hoffman DK, Zhang W, Kuang R, Roden AC, Mansfield AS, Hoeppner LH (2018-05-03). "DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration". Communications Biology. 1 (1): 43. doi:10.1038/s42003-018-0050-6. PMC   5959014 . PMID   29782621.
  27. Gu L, Waliany S, Kane SE (July 2009). "Darpp-32 and its truncated variant t-Darpp have antagonistic effects on breast cancer cell growth and herceptin resistance". PLOS ONE. 4 (7): e6220. Bibcode:2009PLoSO...4.6220G. doi: 10.1371/journal.pone.0006220 . PMC   2704867 . PMID   19593441.
  28. Hamel S, Bouchard A, Ferrario C, Hassan S, Aguilar-Mahecha A, Buchanan M, Quenneville L, Miller W, Basik M (February 2010). "Both t-Darpp and DARPP-32 can cause resistance to trastuzumab in breast cancer cells and are frequently expressed in primary breast cancers". Breast Cancer Research and Treatment. 120 (1): 47–57. doi:10.1007/s10549-009-0364-7. PMID   19301121. S2CID   20958252.
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  30. 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". Journal of Neurochemistry. 79 (5): 1027–32. doi: 10.1046/j.1471-4159.2001.00651.x . PMID   11739615. S2CID   35861963.
  31. 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". The Journal of Biological Chemistry. 282 (10): 7352–9. doi: 10.1074/jbc.M606508200 . PMID   17209049.
  32. Souza BR, Torres KC, Miranda DM, Motta BS, Caetano FS, Rosa DV, Souza RP, Giovani A, Carneiro DS, Guimarães MM, Martins-Silva C, Reis HJ, Gomez MV, Jeromin A, Romano-Silva MA (January 2011). "Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1". Cellular and Molecular Neurobiology. 31 (1): 135–43. doi:10.1007/s10571-010-9562-4. PMC   11498493 . PMID   20838877. S2CID   25500946.

Further reading