PPP1R1B explained

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] DARPP-32 is critical for dopamine dependent striatal synaptic plasticity,[8] possibly by serving as a dopamine-dependent gating mechanism for calcium/CaMKII signaling.[9] 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.

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,[10] 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,[11] and in Parkinson's disease or EPS (Extra-pyramidal symptoms).[12] DARPP-32 levels are decreased in the dorsolateral prefrontal cortex and lymphocytes of both schizophrenia and bipolar disorder patients.[13] [14] [15] This alteration is suggested to be related to the pathology, since antipsychotics do not regulate the expression of DARPP-32.[16] [17]

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.[18]

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.[19]

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.[20] Both isoforms are overexpressed in a number of cancers including those derived from gastric, colon, prostate, esophageal, breast, and lung tissues.[21] [22] 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.[23] [24] [25]

Regulation

Brain-derived neurotrophic factor regulates the expression of DARPP-32.[26] The Akt and CDK5/p35 intracellular pathway is suggested to be involved on this regulation.[27] Also, neuronal calcium sensor-1 was suggested to modulate the expression of DARPP-32.[28]

Discovery

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

Further reading

Notes and References

  1. Web site: 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 . 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 . March 1994 . 8120638 . 6577526 . 10.1523/JNEUROSCI.14-03-00985.1994.
  3. Ouimet CC, Greengard P . Distribution of DARPP-32 in the basal ganglia: an electron microscopic study . Journal of Neurocytology . 19 . 1 . 39–52 . February 1990 . 2191086 . 10.1007/BF01188438 . 33812522 .
  4. Walaas SI, Greengard P . 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 . January 1984 . 6319627 . 6564747 . 10.1523/JNEUROSCI.04-01-00084.1984.
  5. Halpain S, Girault JA, Greengard P . Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices . Nature . 343 . 6256 . 369–72 . January 1990 . 2153935 . 10.1038/343369a0 . 1990Natur.343..369H . 4319592 .
  6. Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P . 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 . November 2000 . 11050161 . 18851 . 10.1073/pnas.220410397 . 2000PNAS...9712840N . free .
  7. Hemmings HC, Greengard P, Tung HY, Cohen P . DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1 . Nature . 310 . 5977 . 503–5 . 1984 . 6087160 . 10.1038/310503a0 . 1984Natur.310..503H . 4307053 .
  8. Yagishita S, Hayashi-Takagi A, Ellis-Davies GC, Urakubo H, Ishii S, Kasai H . A critical time window for dopamine actions on the structural plasticity of dendritic spines . Science . 345 . 6204 . 1616–20 . September 2014 . 25258080 . 4225776 . 10.1126/science.1255514 . 2014Sci...345.1616Y .
  9. Nair AG, Bhalla US, Hellgren Kotaleski J . 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 . September 2016 . 27584878 . 5008828 . 10.1371/journal.pcbi.1005080 . 2016PLSCB..12E5080N . free .
  10. Scott L, Forssberg H, Aperia A, Diaz-Heijtz R . Locomotor effects of a D1R agonist are DARPP-32 dependent in adult but not weanling mice . Pediatric Research . 58 . 4 . 779–83 . October 2005 . 16189209 . 10.1203/01.PDR.0000180553.23507.31 . free .
  11. Svenningsson P, Nairn AC, Greengard P . DARPP-32 mediates the actions of multiple drugs of abuse . The AAPS Journal . 7 . 2 . E353-60 . October 2005 . 16353915 . 2750972 . 10.1208/aapsj070235 .
  12. Clinton SM, Ibrahim HM, Frey KA, Davis KL, Haroutunian V, Meador-Woodruff JH . 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 . October 2005 . 16199832 . 10.1176/appi.ajp.162.10.1859 .
  13. Albert KA, Hemmings HC, Adamo AI, Potkin SG, Akbarian S, Sandman CA, Cotman CW, Bunney WE, Greengard P . Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia . Archives of General Psychiatry . 59 . 8 . 705–12 . August 2002 . 12150646 . 10.1001/archpsyc.59.8.705 . 1672878 .
  14. Ishikawa M, Mizukami K, Iwakiri M, Asada T . 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 . August 2007 . 17521792 . 10.1016/j.pnpbp.2007.04.013 . 27481326 .
  15. Torres KC, Souza BR, Miranda DM, Nicolato R, Neves FS, Barros AG, Dutra WO, Gollob KJ, Correa H, Romano-Silva MA . The leukocytes expressing DARPP-32 are reduced in patients with schizophrenia and bipolar disorder . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 33 . 2 . 214–9 . March 2009 . 19059449 . 10.1016/j.pnpbp.2008.10.020 . 8431767 .
  16. Souza BR, Motta BS, Rosa DV, Torres KC, Castro AA, Comim CM, Sampaio AM, Lima FF, Jeromin A, Quevedo J, Romano-Silva MA . 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 . March 2008 . 17763944 . 10.1007/s11064-007-9470-2 . 27727055 .
  17. 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 . 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 . June 2010 . 20565907 . 2912242 . 10.1186/1477-5751-9-4 . free .
  18. Andersson M, Usiello A, Borgkvist A, Pozzi L, Dominguez C, Fienberg AA, Svenningsson P, Fredholm BB, Borrelli E, Greengard P, Fisone G . 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 . September 2005 . 16162925 . 6725667 . 10.1523/JNEUROSCI.1289-05.2005 .
  19. 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 . Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition . The Journal of Clinical Investigation . 117 . 3 . 672–82 . March 2007 . 17290303 . 1784004 . 10.1172/JCI30413 .
  20. El-Rifai W, Smith MF, Li G, Beckler A, Carl VS, Montgomery E, Knuutila S, Moskaluk CA, Frierson HF, Powell SM . Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP . Cancer Research . 62 . 14 . 4061–4 . July 2002 . 12124342 .
  21. Belkhiri A, Zhu S, El-Rifai W . DARPP-32: from neurotransmission to cancer . Oncotarget . 7 . 14 . 17631–40 . April 2016 . 26872373 . 4951238 . 10.18632/oncotarget.7268 .
  22. Alam SK, Astone M, Liu P, Hall SR, Coyle AM, Dankert EN, Hoffman DK, Zhang W, Kuang R, Roden AC, Mansfield AS, Hoeppner LH . DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration . En . Communications Biology . 1 . 1 . 2018-05-03 . 43 . 29782621 . 5959014 . 10.1038/s42003-018-0050-6 .
  23. Gu L, Waliany S, Kane SE . Darpp-32 and its truncated variant t-Darpp have antagonistic effects on breast cancer cell growth and herceptin resistance . PLOS ONE . 4 . 7 . e6220 . July 2009 . 19593441 . 2704867 . 10.1371/journal.pone.0006220 . 2009PLoSO...4.6220G . free .
  24. Hamel S, Bouchard A, Ferrario C, Hassan S, Aguilar-Mahecha A, Buchanan M, Quenneville L, Miller W, Basik M . 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 . February 2010 . 19301121 . 10.1007/s10549-009-0364-7 . 20958252 .
  25. Belkhiri A, Dar AA, Peng DF, Razvi MH, Rinehart C, Arteaga CL, El-Rifai W . Expression of t-DARPP mediates trastuzumab resistance in breast cancer cells . Clinical Cancer Research . 14 . 14 . 4564–71 . July 2008 . 18579663 . 2842884 . 10.1158/1078-0432.CCR-08-0121 .
  26. Stroppolo A, Guinea B, Tian C, Sommer J, Ehrlich ME . 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 . December 2001 . 11739615 . 10.1046/j.1471-4159.2001.00651.x . 35861963 . free .
  27. Bogush A, Pedrini S, Pelta-Heller J, Chan T, Yang Q, Mao Z, Sluzas E, Gieringer T, Ehrlich ME . 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 . March 2007 . 17209049 . 10.1074/jbc.M606508200 . free .
  28. 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 . Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1 . Cellular and Molecular Neurobiology . 31 . 1 . 135–43 . January 2011 . 20838877 . 10.1007/s10571-010-9562-4 . 25500946 .

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