PPP1R1B
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Location (UCSC) | Chr 17: 39.63 – 39.64 Mb | Chr 11: 98.24 – 98.25 Mb | |||||||
PubMed search | [3] | [4] |
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]
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
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
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]
- ^ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000131771 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000061718 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: PPP1R1B protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)".
- ^ PMID 8120638.
- S2CID 33812522.
- ^ PMID 6319627.
- ^ S2CID 4319592.
- PMID 11050161.
- S2CID 4307053.
- PMID 25258080.
- ^ PMID 27584878.
- PMID 16189209.
- PMID 16353915.
- PMID 16199832.
- S2CID 1672878.
- S2CID 27481326.
- S2CID 8431767.
- S2CID 27727055.
- PMID 20565907.
- PMID 16162925.
- PMID 17290303.
- PMID 12124342.
- PMID 26872373.
- PMID 29782621.
- PMID 19593441.
- S2CID 20958252.
- PMID 18579663.
- S2CID 35861963.
- PMID 17209049.
- S2CID 25500946.
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". The Journal of Biological Chemistry. 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. PMID 16123776.
- Rosack, J (20 September 2002). "DARPP-32 May Be Culprit in Schizophrenia Symptoms". Psychiatric News. 37 (18): 24. Archived from the original on 22 February 2007. Retrieved 3 June 2008.
- Meister B, Askergren J, Tunevall G, Hemmings HC, Greengard P (September 1991). "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". S2CID 36936723.
- Meister B, Schultzberg M, Hemmings HC, Greengard P, Goldstein M, Hökfelt T (October 1991). "Dopamine- and adenosine-3',5'-monophosphate (cAMP)-regulated phosphoprotein of 32 kDa (DARPP-32) in the adrenal gland: immunohistochemical localization". Journal of the Autonomic Nervous System. 36 (1): 75–84. PMID 1721636.
- Meister B, Arvidsson U, Hemmings HC, Greengard P, Hökfelt T (September 1991). "Dopamine- and adenosine-3':5'-monophosphate (cAMP)-regulated phosphoprotein of Mr 32,000 (DARPP-32) in the retina of cat, monkey and human". Neuroscience Letters. 131 (1): 66–70. S2CID 1735579.
- 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. S2CID 4319592.
- 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. S2CID 33812522.
- Girault JA, Hemmings HC, Williams KR, Nairn AC, Greengard P (December 1989). "Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II". The Journal of Biological Chemistry. 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. S2CID 4307053.
- 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. PMID 6319627.
- 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. PMID 8120638.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. PMID 8125298.
- Kwon YG, Huang HB, Desdouits F, Girault JA, Greengard P, Nairn AC (April 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". Proceedings of the National Academy of Sciences of the United States of America. 94 (8): 3536–41. PMID 9108011.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. PMID 9373149.
- Mayerhofer A, Hemmings HC, Snyder GL, Greengard P, Boddien S, Berg U, Brucker C (January 1999). "Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro". The Journal of Clinical Endocrinology and Metabolism. 84 (1): 257–64. S2CID 41955399.
- Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC, Nairn AC, Greengard P (December 1999). "Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons". Nature. 402 (6762): 669–71. S2CID 4387962.
- Mayerhofer A, Fritz S, Grünert R, Sanders SL, Duffy DM, Ojeda SR, Stouffer RL (December 2000). "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". The Journal of Clinical Endocrinology and Metabolism. 85 (12): 4750–7. PMID 11134138.
- 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.
- Beckler A, Moskaluk CA, Zaika A, Hampton GM, Powell SM, Frierson HF, El-Rifai W (October 2003). "Overexpression of the 32-kilodalton dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein in common adenocarcinomas". Cancer. 98 (7): 1547–51. S2CID 21961891.
- Varis A, Zaika A, Puolakkainen P, Nagy B, Madrigal I, Kokkola A, Väyrynen A, Kärkkäinen P, Moskaluk C, El-Rifai W, Knuutila S (April 2004). "Coamplified and overexpressed genes at ERBB2 locus in gastric cancer". International Journal of Cancer. 109 (4): 548–53. S2CID 29950388.
- 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. S2CID 35861963.
- 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. PMID 17209049.
- 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. S2CID 25500946.
- 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. S2CID 1672878.
- 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. S2CID 27481326.
- 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. S2CID 27727055.
- 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. PMID 20565907.
- 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. S2CID 8431767.