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 PPP1R1Bgene.[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 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]
^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. PMID2191086. S2CID33812522.
^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. PMID16199832.
^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. PMID12150646. S2CID1672878.
^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. PMID17521792. S2CID27481326.
^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. PMID19059449. S2CID8431767.
^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. PMID17763944. S2CID27727055.
^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. PMID19301121. S2CID20958252.
^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. PMID20838877. S2CID25500946.
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". Journal of Endocrinological Investigation. 14 (8): 655–61. doi:10.1007/bf03347888. PMID1663529. S2CID36936723.
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. doi:10.1016/0165-1838(91)90132-M. PMID1721636.
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. doi:10.1016/0304-3940(91)90338-T. PMID1791981. S2CID1735579.
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. PMID2191086. S2CID33812522.
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. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
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. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
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. PMID12124342.
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. doi:10.1002/cncr.11654. PMID14508844. S2CID21961891.
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. doi:10.1002/ijc.20001. PMID14991576. S2CID29950388.
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. PMID20838877. S2CID25500946.
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. PMID12150646. S2CID1672878.
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. PMID17521792. S2CID27481326.
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. PMID17763944. S2CID27727055.
