Nội dung được dịch bởi AI, chỉ mang tính chất tham khảo
Vai trò của WNK trong việc điều chỉnh hoạt động vận chuyển KCl ở tế bào hồng cầu từ những cá nhân bình thường và bệnh nhân mắc bệnh hồng cầu hình liềm
Tóm tắt
Hoạt động bất thường của hệ vận chuyển KCl (KCC) trong tế bào hồng cầu liên quan đến cơ chế bệnh sinh của bệnh hồng cầu hình liềm (SCA). Sự mất mát chất hòa tan do KCC gây ra làm co lại tế bào, đồng thời tăng nồng độ HbS và thúc đẩy quá trình polymer hóa HbS. KCC trong tế bào hồng cầu cũng phản ứng với nhiều kích thích khác nhau bao gồm pH, thể tích, ure, và áp suất oxy, và sự điều hòa liên quan đến việc phosphoryl hóa protein. Mục tiêu chính của nghiên cứu này là điều tra vai trò của con đường WNK/SPAK/OSR1 trong các tế bào hồng cầu hình liềm. Chất ức chế WNK toàn phần WNK463 kích thích KCC với EC50 là 10,9 ± 1,1 nM và 7,9 ± 1,2 nM ở tế bào hồng cầu hình liềm và tế bào hồng cầu bình thường, tương ứng. Các chất ức chế SPAK/OSR1 có tác động rất nhỏ. Tác động của WNK463 không cộng thêm với các chất ức chế kinase khác (staurosporine và N-ethylmaleimide). Tác động của nó phần lớn bị hủy bỏ bởi việc điều trị trước bằng chất ức chế phosphatase calyculin A. WNK463 cũng làm giảm ảnh hưởng của các kích thích KCC sinh lý (pH, thể tích, ure) và loại bỏ bất kỳ phản ứng nào của KCC đối với sự thay đổi áp suất oxy. Cuối cùng, mặc dù các kinase protein đã được chứng minh có liên quan đến việc điều chỉnh sự phơi bày phosphatidylserine, WNK463 không có tác động. Các phát hiện cho thấy vai trò chủ yếu của WNK trong việc kiểm soát KCC trong các tế bào hồng cầu hình liềm nhưng không có sự tham gia rõ ràng của SPAK/OSR1 ở giai đoạn hạ nguồn. Việc hiểu rõ hơn về các cơ chế sẽ thông tin về bệnh sinh trong khi việc điều chỉnh hoạt động của WNK đại diện cho một phương pháp điều trị tiềm năng.
Từ khóa
#bệnh hồng cầu hình liềm #KCl #hệ vận chuyển #WNK #SPAK #OSR1Tài liệu tham khảo
Alessi DR, Zhang J, Khanna A, Hochdorfer T, Shang Y, Kahle KT (2014) The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Sci Signal 7:1–10
Bize I, Guvenc B, Robb A, Buchbinder G, Brugnara C (1999) Serine/threonine protein phosphatases and regulation of K-Cl cotransport in human erythrocytes. Am J Physiol 277:C926–C936
Bize I, Guvenc B, Buchbinder G, Brugnara C (2000) Stimulation of human erythrocyte K-Cl cotransport and protein phosphatase type 2A by n-ethylmaleimide: role of intracellular Mg2+. J Membr Biol 177:159–168
Brugnara C, Bunn HF, Tosteson DC (1986) Regulation of erythrocyte cation and water content in sickle cell anemia. Science 232:388–390
Bunn HF, Forget BG (1986) Hemoglobin: molecular, genetic and clinical aspects. Saunders, Philadelphia
Canessa M, Spalvins A, Nagel RL (1986) Volume-dependent and NEM-stimulated K+, Cl- transport is elevated in oxygenated SS, SC and CC human red cells. FEBS Lett 200:197–202
Chu H, McKenna MM, Krump NA, Zheng S, Mendelsohn L, Thien SL, Garrett LJ, Bodine DM, Low PS (2016) Reversible binding of hemoglobin to band 3 constitutes the molecular switch that mediates O2 regulation of erythrocyte properties. Blood 128:2708–2716
Conway LC, Cardarelli RA, Moore YE, Jones K, McWilliams LJ, Baker DJ, Burnham MP, Burli RW, Wang Q, Brandon NJ, Moss SJ, Deeb TZ (2017) N-ethylmaleimide increases KCC2 cotransporter activity by modulating transporter phosphorylation. J Biol Chem 292:21253–21263
Cossins AR, Gibson JS (1997) Volume-sensitive transport systems and volume homeostasis in vertebrate red blood cells. J Exp Biol 200:343–352
Cossins AR, Weaver YR, Lykkeboe G, Nielsen OB (1994) Role of protein phosphorylation in control of K flux pathways of trout red blood cells. Am J Physiol 267:C1641–C1650
Crable SC, Hammond SM, Papes R, Rettig RK, Zhou G-P, Gallagher PG, Joiner CH, Anderson KP (2005) Multiple isoforms of the KCl cotransporter are expressed in sickle and normal erythroid cells. Exp Hematol 33:624–631
Cytlak UM, Hannemann A, Rees DC, Gibson JS (2013) Identification of the Ca2+ entry pathway involved in deoxygenation-induced phosphatidylserine exposure in red blood cells from patients with sickle cell disease. Pflugers Arch - Eur J Physiol 465:1651–1660
De Franceschi L, Fumagalli L, Olivieri O, Corrocher R, Lowell CA, Berton G (1997) Deficiency of Src family kinases Fgr and Hck results in activation of erythrocyte K/Cl cotransport. J Clin Investig 99:220–227
de los Heros P, Kahle KT, Rinehart J, Bobadilla NA, Vazquez N, San Cristobal P, Mount DB, Lifton RP, Hebert SC, Gamba G (2006) WNK3 bypasses the tonicity requirement for K-Cl cotransporter activation via a phosphatase-dependent pathway. Proc Natl Acad Sci U S A 103:1976–1981
de los Heros P, Alessi DR, Gourlay R, Campbell DG, Deak M, Macartney TJ, Kahle KT, Zhang J (2014) The WNK-regulated SPAK-OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. Biochem J 458:559–573
Delpire E, Gagnon KBE (2008) SPAK and OSR1: STE20 kinases involved in the regulation of ion homeostasis and volume control in mammalian cells. Biochem J 409:321–331
Dowd BFX, Forbush B (2003) PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-l cotransporter (NKCC1). J Biol Chem 278:27347–27353
Dunham PB, Ellory JC (1980) Chloride-activated potassium transport in human erythrocytes. Proc Natl Acad Sci U S A 77(1711-1715):1980
Eaton JW, Hofrichter J (1987) Hemoglobin S gelation and sickle cell disease. Blood 70:1245–1266
Ellory JC, Dunham PB (1982) Logue PJ, and Stewart GW (1988) Anion-dependent cation transport in erythrocytes. Phil Trans R Soc Lond B 299:483–495
Ellory JC, Hall AC (1988) Human red cell volume regulation in hypotonic media. Comp Biochem Physiol 90:533–537
Flatman PW, Adragna NC, Lauf PK (1996) Role of protein kinases in regulating sheep erythrocyte K-Cl cotransport. Am J Physiol 271:C255–C263
Gamba G (2005) Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev 85:423–493
Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, Brenner BM, Hebert SC (1993) Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci U S A 90:2749–2753
Gibson JS, Ellory JC (2003) K+-Cl- cotransport in vertebrate red cells. In: Bernhardt I, Ellory JC (eds) Red cell membrane transport in health and disease. Springer Verlag, Berlin, pp 197–220
Gibson JS, Speake PF, Ellory JC (1998) Differential oxygen sensitivity of the K+-Cl- cotransporter in normal and sickle human red blood cells. J Physiol 511:225–234
Gibson JS, Cossins AR, Ellory JC (2000) Oxygen-sensitive membrane transporters in vertebrate red cells. J Exp Biol 203:1395–1407
Gibson JS, Ellory JC, Adragna NC, Lauf PK (2009) Pathophysiology of the K+-Cl- cotransporters: paths to discovery and overview. In: Delpire FJA-LE (ed) Physiology and pathology of chloride transporters and channels in the nervous system: from molecules to disease. Academic, London, pp 27–42
Gibson JS, Al Balushi HWM, Hannemann A, Rees D (2015) Sickle cell disease and 5HMF: the search for effective treatments. Drugs Future 40:817–826
Hall AC, Ellory JC (1986) Evidence for the presence of volume-sensitive KCl transport in 'young' human red cells. Biochim Biophys Acta 858:317–320
Hannemann A, Flatman PW (2011) Phosphorylation and transport in the Na-K-2Cl cotransporters, NKCC1 and NKCC2A, compared in HEK-293 cells. PLoS ONE 6:e17992
Hoffman EK, Sjoholm C, Simonsen LO (1981) Anion-cation co-transport and volume regulation in Ehrlich ascites tumour cells. J Physiol 319:94P–95P
Jennings ML, Al-Rohil N (1990) Kinetics of activation and inactivation of swelling-stimulated K/Cl transport: the volume-sensitive parameter is the rate constant for inactivation. J Gen Physiol 95:1021–1040
Jennings ML, Schulz RK (1991) Okadaic acid inhibition of KCl cotransport: evidence that protein dephosphorylation is necessary for activation of transport by either swelling or N-ethylmaleimide. J Gen Physiol 97:799–817
Joiner CH, Rettig RK, Jiang M, Franco RS (2004) KCl cotransport mediates abnormal sulfhydryl-dependent volume regulation in sickle erythrocytes. Blood 104:2954–2960
Kahle KT, Rinehart J, Ring A, Gimenez I, Gamba G, Hebert SC, Lifton RP (2006) WNK protein kinases modulate cellular Cl- flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters. Physiology 21:326–335
Kaji DM, Gasson C (1995) Urea activation of K-Cl cotransport in human erythrocytes. Am J Physiol 268:C1018–C1025
Lauf PK, Theg BE (1980) A chloride dependent K+ flux induced by N-ethylmaleimide in genetically low K+ sheep and goat erythrocytes. Biochem Biophys Res Commun 92:1422–1428
Lauf PK, Bauer J, Adragna NC, Fujise H, Martin A, Zade-Oppen M, Ryu KH, Delpire E (1992) Erythrocyte K-Cl cotransport: properties and regulation. Am J Physiol 263:C917–C932
Low PS, Rathinavelu P, Harrison ML (1993) Regulation of glycolysis via reversible enzyme binding to the membrane protein, band 3. J Biol Chem 268:14627–14631
Merciris P, Hardy-Dessources MD, Giraud F (2001) Deoxygenation of sickle cells stimulates Syk tyrosine kinase and inhibits a membrane tyrosine phosphatase. Blood 98:3121–3127
Merciris P, Claussen WJ, Joiner CH, Giraud F (2003) Regulation of K-Cl cotransport by Syk and Src protein tyrosine kinases in deoxygenated sickle cells. Pflugers Arch - Eur J Physiol 446:232–238
Motais R, Garcia-Romeu F, Borgese F (1987) The control of Na/H exchange by molecular oxygen in trout erythrocytes. J Gen Physiol 90:197–207
Muzyamba MC, Cossins AR, Gibson JS (1999) Regulation of Na+-K+-2Cl- cotransport in turkey red cells: the role of oxygen tension and protein phosphorylation. J Physiol 517:421–429
Pan D, Kalfa TA, Wang D, Risinger M, Crable S, Ottlinger A, Chandra S, Mount DB, Hubner CA, Franco RS, Joiner CH (2011) K-Cl cotransporter gene expression during human and murine erythroid differentiation. J Biol Chem 286:30492–30503
Pellegrino CM, Rybicki AC, Musto S, Nagel RL, Schwartz RS (1998) Molecular identification of erythroid K:Cl cotransporter in human and mouse erythroleukemic cells. Blood Cell Mol Dis 24:31–40
Piechotta K, Lu J, Delpire E (2002) Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem 277:50812–50819
Rees DC, Williams TN, Gladwin MT (2010) Sickle-cell disease. Lancet 376:2018–2031
Richardson C, Alessi DR (2008) The regulation of salt transport and blood pressure by the WNK-SPAK/ORS1 signalling pathway. J Cell Sci 121:3292–3304
Rinehart J, Maksimova YD, Tanis JE, Stone KL, Hodson CA, Zhang J, Risinger M, Pan W, Wu D, Colangelo CM, Forbush B, Joiner CH, Gulcicek EE, Gallagher PG, Lifton RP (2009) Sites of regulated phosphorylation that control K-Cl cotransporter activity. Cell 138:525–536
Rust MB, Alper SL, Rudhard Y, Shmukler BE, Vicente R, Brugnara C, Trudel M, Jentsch TJ, Hubner CA (2007) Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. J Clin Investig 117:1708–1717
Starke LC, Jennings ML (1993) KCl cotransport in rabbit red cells: further evidence for regulation by protein phosphatase type I. Am J Physiol 264:C118–C124
Steinberg MH (1999) Management of sickle cell disease. N Engl J Med 340:1021–1030
Weaver YR, Cossins AR (1995) Protein tyrosine phosphorylation regulates the KCl cotransporter in trout red cells. J Physiol 489P:100–101P
Wesseling MC, Wagner-Britz L, Nguyen DB, Asanidze S, Mutua J, Mohamed N, Hanf B, Ghashghaeinia M, Kaestner L, Bernhardt I (2016) Novel insights into the regulation of phosphatidylserine exposure in human red blood cells. Cell Physiol Biochem 39:1941–1954
Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP (2001) Human hypertension caused by mutations in WNK kinases. Science 293:1107–1112
Xu JC, Lytle C, Zhu TT, Payne JA, Benz EJ, Forbush BI (1994) Molecular cloning and functional expression of the bumetanide-sensitive Na-K-Cl cotransporter. Proc Natl Acad Sci U S A 91:2201–2205
Xu B, English JM, Wilsbacher JL, Stippec S, Goldsmith EJ, Cobb MH (2000) WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J Biol Chem 275:16795–16801
Yagi YI, Avbe K, Ikebukuro K, Sode K (2009) Kinetic mechanism and inhibitor characterization of WNK1 kinase. Biochemistry 48:10255–10266
Yamada K, Park HM, Rigel DF, DiPetrillo K, Whalen EJ, Anisowicz A, Beil M, Berstler J, Brocklehurst CE, Burdick DA, Caplan SL, Capparelli MP, Chen G, Chen W, Dale B, Deng L, Fu F, Hamamatsu N, Harasaki K, Herr T, Hoffmann P, Hu QY, Huang WJ, Idamakanti N, Imase H, Iwaki Y, Jain M, Jeyaseelan J, Kato M, Kaushik VK, Kohls D, Kunjathoor V, LaSala D, Lee J, Liu J, Luo Y, Ma F, Mo R, Mowbray S, Mogi M, Ossola F, Pandey P, Patel SJ, Raghavan S, Salem B, Shanado YH, Trakshel GM, Turner G, Wakai H, Wang C, Weldon S, Wielicki JB, Xie X, Xu L, Yagi YI, Yasoshima K, Yin J, Yowe D, Zhang JH, Zheng G, Monovich L (2016) Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol 12:896–903
Zagorska A, Pozo-Guisado E, Boudeau J, Vitari AC, Rafiqi FH, Thastrup J, Dean M, Campbell DG, Morrice NA, Prescott AR, Alessi DR (2007) Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress. J Cell Biol 176:89–100
Zhang J, Gao G, Begum G, Wang J, Khanna AR, Shmukler BE, Daubner GM, de los Heros P, Davies P, Varghese J, Bhuiyan MI, Duan D, Alper SL, Sun D, Elledge SJ, Alessi DR, Kahle KT (2016) Functional kinomics establishes a critical mode of volume-sensitive cation-Cl- cotransporter regulation in the mammalian brain. Sci Rep 6:35986
Zheng S, Krump NA, McKenna MM, Li Y-H, Hannemann A, Garrett LJ, Gibson JS, Bodine DM, Low PS (2019) Regulation of erythrocyte Na+K+2Cl- cotransport by an oxygen-switched kinase cascade. J Biol Chem 294:2519–2528