Calcineurina

A calcineurina (CN) é un encima proteína fosfatase, tamén chamada proteína fosfatase 3, e serina-treonina fosfatase dependente de calcio.^[2] Activa as células T do sistema inmunitario e pode ser bloqueada por diversos fármacos. A calcineurina activa, desfosforilándoo, ao factor nuclear das células T activadas citoplasmático (NFATc), que é un factor de transcrición que se encontra no citoplasma e é despois translocado ao núcleo, onde regula á alza a expresión da interleucina 2 (IL-2), a cal, á súa vez, estimula a resposta de células T. A calcineurina é a diana dun tipo de fármacos chamados inhibidores da calcineurina, entre os cales están a ciclosporina, Pimecrolimus e Tacrolimus.

Estrutura

A calcineurina é un heterodímero formado por unha subuinidade de 61-kDa catalítica que se une á calmodulina, chamada calcineurina A, e unha subunidade de 19-kDa regulatoria que se une ao Ca²⁺, chamada calcineurina B. Hai tres isocimas da subunidade catalítica, cada unha das cales está codificada por un xene separado (PPP3CA, PPP3CB, e PPP3CC) e dúas isoformas da subunidade regulatoria, tamén codificadas por xenes separados (PPP3R1, PPP3R2).

proteína fosfatase 3, subunidade catalítica, isocima alfa
Identificadores
Símbolo	PPP3CA
Símbolos alt.	CALN, CALNA
Entrez	5530
HUGO	9314
OMIM	114105
RefSeq	NM_000944
UniProt	Q08209
Outros datos
Número EC	3.1.3.16
Locus	Cr. 4 q24

proteína fosfatase 3, subunidade catalítica, isocima beta
Identificadores
Símbolo	PPP3CB
Símbolos alt.	CALNB
Entrez	5532
HUGO	9315
OMIM	114106
RefSeq	NM_021132
UniProt	P16298
Outros datos
Número EC	3.1.3.16
Locus	Cr. 10 q22.2

proteína fosfatase 3, subunidade catalítica, isocima gamma
Identificadores
Símbolo	PPP3CC
Entrez	5533
HUGO	9316
OMIM	114107
RefSeq	NM_005605
UniProt	P48454
Outros datos
Número EC	3.1.3.16
Locus	Cr. 8 p21.3

proteína fosfatase 3, subinidade regulatoria B, alfa
Identificadores
Símbolo	PPP3R1
Entrez	5534
HUGO	9317
OMIM	601302
RefSeq	NM_000945
UniProt	P63098
Outros datos
Número EC	3.1.3.16
Locus	Cr. 2 p14

proteína fosfatase 3, subunidade regulatoria B, beta
Identificadores
Símbolo	PPP3R2
Entrez	5535
HUGO	9318
OMIM	613821
RefSeq	NM_147180
UniProt	Q96LZ3
Outros datos
Número EC	3.1.3.16
Locus	Cr. 9 q31

Funcionamento

Cando unha célula presentadora de antíxenos interacciona cun receptor de células T situado na superficie dunha célula T, prodúcese un incremento do nivel citoplasmático de calcio, o cal^[3] activa a calcineurina, ao unirse á súa subunidade regulatoria e activar a unión da calmodulina. A calcineurina induce varios factores de transcrición (NFATs) que son importantes na transcrición dos xenes de IL-2. O IL-2 activa os linfocitos T axudantes e induce a produción doutras citocinas. Deste modo, controla a acción dos linfocitos citotóxicos. A cantidade de IL-2 producida polas células T axudantes crese que inflúe significativamente na amplitude que vai ter a resposta inmune.

Importancia clínica

Enfermidades reumáticas

Os inhibidores da calcineurina prescríbense para tratar a artrite reumatoide adulta en solitario ou en combinación co metrotexato. Tamén se prescribe para: artrite psoriática, psoríase, enfermidade de Behçet ocular aguda, artrite idiopática xuvenil, polimiosite e dermatomiosite xuvenil e adulta, lupus eritematoso xuvenil e adulto, nefrite lupus membranoso adulta, esclerose sistémica, anemia aplástica, síndrome nefrótica resistente a esteroides, dermatite atópica, asma dependente de corticoides grave, colite ulcerativa grave, pemphigus vulgaris, myasthenia gravis, e enfermidade do ollo seco, con ou sen síndrome de Sjögren (administrada como emulsión oftálmica).

Esquizofrenia

A calcineurina está asociada aos receptores de varios compostos presentes no cerebro como NMDA, dopamina e GABA.^[4] Un experimento realizado con ratos alterados xenetricamente que non podían producir calcineurina atopou que estes mostraban síntomas similares aos da esquizofrenia humana: trastornos de memoria, déficits de atención, comportamento social anormal, e outras anormalidades características da esquizofrenia.^[5]

Diabetes

A calcineurina, xunto co NFAT, pode mellorar a función das células beta do páncreas diabético.^[6]^[7] O fármaco Tacrolimus contribúe ao frecuente desenvolvemento de diabete despois dun transplante renal.^[8]

Outros

A sinalización calcineurina/Nfat é necesaria para o funcionamento e a maduración perinatal dos pulmóns.^[9]

Interaccións

A calcineurina interacciona con DSCR1^[10] e AKAP5.^[11]

Notas

↑ PDB 1AUI; Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW (December 1995). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. PMID 8524402. doi:10.1038/378641a0.
↑ Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L. (March 2005). "Crystal Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis". Mol Biol Rep 32 (1): 41–45. PMID 15865209. doi:10.1007/s11033-004-4250-4.
↑ Yamashita M, Katsumata M, Iwashima M, Kimura M, Shimizu C, Kamata T, Shin T, Seki N, Suzuki S, Taniguchi M, Nakayama T (June 2000). "T Cell Receptor–Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex". J. Exp. Med. 191 (11): 1869–79. PMC 2213529. PMID 10839803. doi:10.1084/jem.191.11.1869.
↑ Bannai, H.; Levi, S.; Schweizer, C.; Inoue, T.; Launey, T.; Racine, V.; Sibarita, JB; Mikoshiba, K; Triller, A (2009). "Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics". Neuron 62 (5): 670–682. PMID 19524526. doi:10.1016/j.neuron.2009.04.023.
↑ Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S (July 2003). "Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8987–92. PMC 166425. PMID 12851457. doi:10.1073/pnas.1432926100.
↑ Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, Crabtree GR, Kim SK (September 2006). "Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function". Nature 443 (7109): 345–9. PMID 16988714. doi:10.1038/nature05097.
↑ Heit JJ (October 2007). "Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics". BioEssays 29 (10): 1011–21. PMID 17876792. doi:10.1002/bies.20644.
↑ Crutchlow MF, Bloom RD (2007). "Transplant-associated hyperglycemia: a new look at an old problem". Clin J Am Soc Nephrol 2 (2): 343–55. PMID 17699434. doi:10.2215/CJN.03671106.
↑ Davé V, Childs T, Xu Y, Ikegami M, Besnard V, Maeda Y, Wert SE, Neilson JR, Crabtree GR, Whitsett JA (October 2006). "Calcineurin/Nfat signaling is required for perinatal lung maturation and function". J. Clin. Invest. 116 (10): 2597–609. PMC 1570374. PMID 16998587. doi:10.1172/JCI27331.
↑ Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (July 2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. PMID 10861295. doi:10.1093/hmg/9.11.1681.
↑ Kashishian A, Howard M, Loh C, Gallatin WM, Hoekstra MF, Lai Y (October 1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. PMID 9765270. doi:10.1074/jbc.273.42.27412.

Véxase tamén

Outros artigos

Cottrell JR, Levenson JM, Kim SH, Gibson HE, Richardson KA, Sivula M, Li B, Ashford CJ, Heindl KA, Babcock RJ, Rose DM, Hempel CM, Wiig KA, Laeng P, Levin ME, Ryan TA, Gerber DJ (July 2013). "Working Memory Impairment in Calcineurin Knock-out Mice Is Associated with Alterations in Synaptic Vesicle Cycling and Disruption of High-Frequency Synaptic and Network Activity in Prefrontal Cortex". J. Neurosci. 33 (27): 10938–49. PMID 23825400. doi:10.1523/JNEUROSCI.5362-12.2013.
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Kincaid RL, Giri PR, Higuchi S; et al. (1990). "Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods". J. Biol. Chem. 265 (19): 11312–9. PMID 2162844.
Guerini D, Klee CB (1990). "Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain". Proc. Natl. Acad. Sci. U.S.A. 86 (23): 9183–7. PMC 298458. PMID 2556704. doi:10.1073/pnas.86.23.9183.
Kincaid RL, Nightingale MS, Martin BM (1988). "Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin". Proc. Natl. Acad. Sci. U.S.A. 85 (23): 8983–7. PMC 282646. PMID 2848250. doi:10.1073/pnas.85.23.8983.
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Shibasaki F, McKeon F (1995). "Calcineurin functions in Ca(2+)-activated cell death in mammalian cells". J. Cell Biol. 131 (3): 735–43. PMC 2120616. PMID 7593193. doi:10.1083/jcb.131.3.735.
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Kissinger CR, Parge HE, Knighton DR; et al. (1996). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. PMID 8524402. doi:10.1038/378641a0.
Wang MG, Yi H, Guerini D; et al. (1997). "Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21→q22 and 2p16→p15 respectively". Cytogenet. Cell Genet. 72 (2–3): 236–41. PMID 8978785. doi:10.1159/000134198.
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Kashishian A, Howard M, Loh C; et al. (1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. PMID 9765270. doi:10.1074/jbc.273.42.27412.
Wang HG, Pathan N, Ethell IM; et al. (1999). "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science 284 (5412): 339–43. PMID 10195903. doi:10.1126/science.284.5412.339.
Fuentes JJ, Genescà L, Kingsbury TJ; et al. (2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. PMID 10861295. doi:10.1093/hmg/9.11.1681.
Hartley JL, Temple GF, Brasch MA (2001). "DNA Cloning Using In Vitro Site-Specific Recombination". Genome Res. 10 (11): 1788–95. PMC 310948. PMID 11076863. doi:10.1101/gr.143000.
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Siddiq A, Miyazaki T, Takagishi Y; et al. (2001). "Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism". Endocrinology 142 (5): 1752–9. PMID 11316738. doi:10.1210/en.142.5.1752.

Ligazóns externas

Calcineurin Medical Subject Headings (MeSH) na Biblioteca Nacional de Medicina dos EUA.

[pmid8524402-1] PDB 1AUI; Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW (December 1995). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. PMID 8524402. doi:10.1038/378641a0.

[pmid15865209-2] Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L. (March 2005). "Crystal Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis". Mol Biol Rep 32 (1): 41–45. PMID 15865209. doi:10.1007/s11033-004-4250-4.

[pmid10839803-3] Yamashita M, Katsumata M, Iwashima M, Kimura M, Shimizu C, Kamata T, Shin T, Seki N, Suzuki S, Taniguchi M, Nakayama T (June 2000). "T Cell Receptor–Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex". J. Exp. Med. 191 (11): 1869–79. PMC 2213529. PMID 10839803. doi:10.1084/jem.191.11.1869.

[4] Bannai, H.; Levi, S.; Schweizer, C.; Inoue, T.; Launey, T.; Racine, V.; Sibarita, JB; Mikoshiba, K; Triller, A (2009). "Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics". Neuron 62 (5): 670–682. PMID 19524526. doi:10.1016/j.neuron.2009.04.023.

[pmid12851457-5] Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S (July 2003). "Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8987–92. PMC 166425. PMID 12851457. doi:10.1073/pnas.1432926100.

[pmid16988714-6] Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, Crabtree GR, Kim SK (September 2006). "Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function". Nature 443 (7109): 345–9. PMID 16988714. doi:10.1038/nature05097.

[pmid17876792-7] Heit JJ (October 2007). "Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics". BioEssays 29 (10): 1011–21. PMID 17876792. doi:10.1002/bies.20644.

[pmid17699434-8] Crutchlow MF, Bloom RD (2007). "Transplant-associated hyperglycemia: a new look at an old problem". Clin J Am Soc Nephrol 2 (2): 343–55. PMID 17699434. doi:10.2215/CJN.03671106.

[pmid16998587-9] Davé V, Childs T, Xu Y, Ikegami M, Besnard V, Maeda Y, Wert SE, Neilson JR, Crabtree GR, Whitsett JA (October 2006). "Calcineurin/Nfat signaling is required for perinatal lung maturation and function". J. Clin. Invest. 116 (10): 2597–609. PMC 1570374. PMID 16998587. doi:10.1172/JCI27331.

[pmid10861295-10] Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (July 2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. PMID 10861295. doi:10.1093/hmg/9.11.1681.

[pmid9765270-11] Kashishian A, Howard M, Loh C, Gallatin WM, Hoekstra MF, Lai Y (October 1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. PMID 9765270. doi:10.1074/jbc.273.42.27412.

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