Biology:PPP1R1B

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Short description: Protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[9]

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 intracelular 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]

Interactive pathway map

References

  1. ↑ 1.0 1.1 "Entrez Gene: PPP1R1B protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=84152. 
  2. ↑ 2.0 2.1 "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. doi:10.1523/JNEUROSCI.14-03-00985.1994. PMID 8120638. 
  3. ↑ "Distribution of DARPP-32 in the basal ganglia: an electron microscopic study". Journal of Neurocytology 19 (1): 39–52. February 1990. doi:10.1007/BF01188438. PMID 2191086. 
  4. ↑ 4.0 4.1 "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. doi:10.1523/JNEUROSCI.04-01-00084.1984. PMID 6319627. 
  5. ↑ 5.0 5.1 "Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices". Nature 343 (6256): 369–72. January 1990. doi:10.1038/343369a0. PMID 2153935. Bibcode: 1990Natur.343..369H. 
  6. ↑ "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. doi:10.1073/pnas.220410397. PMID 11050161. Bibcode: 2000PNAS...9712840N. 
  7. ↑ "DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1". Nature 310 (5977): 503–5. 1984. doi:10.1038/310503a0. PMID 6087160. Bibcode: 1984Natur.310..503H. 
  8. ↑ "A critical time window for dopamine actions on the structural plasticity of dendritic spines". Science 345 (6204): 1616–20. September 2014. doi:10.1126/science.1255514. PMID 25258080. Bibcode: 2014Sci...345.1616Y. 
  9. ↑ 9.0 9.1 "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. doi:10.1371/journal.pcbi.1005080. PMID 27584878. Bibcode: 2016PLSCB..12E5080N. 
  10. ↑ "Locomotor effects of a D1R agonist are DARPP-32 dependent in adult but not weanling mice". Pediatric Research 58 (4): 779–83. October 2005. doi:10.1203/01.PDR.0000180553.23507.31. PMID 16189209. 
  11. ↑ "DARPP-32 mediates the actions of multiple drugs of abuse". The AAPS Journal 7 (2): E353-60. October 2005. doi:10.1208/aapsj070235. PMID 16353915. 
  12. ↑ "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. doi:10.1176/appi.ajp.162.10.1859. PMID 16199832. 
  13. ↑ "Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia". Archives of General Psychiatry 59 (8): 705–12. August 2002. doi:10.1001/archpsyc.59.8.705. PMID 12150646. 
  14. ↑ "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. doi:10.1016/j.pnpbp.2007.04.013. PMID 17521792. 
  15. ↑ "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. doi:10.1016/j.pnpbp.2008.10.020. PMID 19059449. 
  16. ↑ "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. doi:10.1007/s11064-007-9470-2. PMID 17763944. 
  17. ↑ "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. doi:10.1186/1477-5751-9-4. PMID 20565907. 
  18. ↑ "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. doi:10.1523/JNEUROSCI.1289-05.2005. PMID 16162925. 
  19. ↑ "Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition". The Journal of Clinical Investigation 117 (3): 672–82. March 2007. doi:10.1172/JCI30413. PMID 17290303. 
  20. ↑ "Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP". Cancer Research 62 (14): 4061–4. July 2002. PMID 12124342. http://cancerres.aacrjournals.org/content/62/14/4061.short. 
  21. ↑ "DARPP-32: from neurotransmission to cancer". Oncotarget 7 (14): 17631–40. April 2016. doi:10.18632/oncotarget.7268. PMID 26872373. 
  22. ↑ "DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration" (in En). Communications Biology 1 (1): 43. 2018-05-03. doi:10.1038/s42003-018-0050-6. PMID 29782621. 
  23. ↑ "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. doi:10.1371/journal.pone.0006220. PMID 19593441. Bibcode: 2009PLoSO...4.6220G. 
  24. ↑ "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. doi:10.1007/s10549-009-0364-7. PMID 19301121. 
  25. ↑ "Expression of t-DARPP mediates trastuzumab resistance in breast cancer cells". Clinical Cancer Research 14 (14): 4564–71. July 2008. doi:10.1158/1078-0432.CCR-08-0121. PMID 18579663. 
  26. ↑ "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. doi:10.1046/j.1471-4159.2001.00651.x. PMID 11739615. 
  27. ↑ "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. doi:10.1074/jbc.M606508200. PMID 17209049. 
  28. ↑ "Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1". Cellular and Molecular Neurobiology 31 (1): 135–43. January 2011. doi:10.1007/s10571-010-9562-4. PMID 20838877. 

Further reading




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