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Properties of Na,K-ATPase in cerebellum of male and female rats: effects of acute and prolonged diabetes

Molecular and Cellular Biochemistry volume 425, pages 25–36 (2017)Cite this article

Abstract

The present study was oriented to gender specificity of Na,K-ATPase in cerebellum, the crucial enzyme maintaining the intracellular homeostasis of Na ions in healthy and diabetic Wistar rats. The effects of diabetes on properties of the Na,K-ATPase in cerebellum derived from normal and streptozotocin (STZ)-diabetic rats of both genders were investigated. The samples were excised at different time intervals of diabetes induced by STZ (65 mg kg−1) for 8 days and 16 weeks. In acute 8-day-lasting model of diabetes, Western blot analysis showed significant depression of α1 isoform of Na,K-ATPase in males only. On the other hand, concerning the activity, the enzyme seems to be resistant to the acute model of diabetes in both genders. Prolongation of diabetes to 16 weeks was followed by increasing the number of active molecules of Na,K-ATPase exclusively in females as indicated by enzyme kinetic studies. Gender specificity was observed also in nondiabetic animals revealing higher Na,K-ATPase activity in control males probably caused by higher number of active enzyme molecules as indicated by increased value of V max when comparing to control female group. This difference seems to be age dependent: at the age of 16 weeks, the V max value in females was higher by more than 90%, whereas at the age of 24 weeks, this difference amounted to only 28%. These data indicate that the properties of Na,K-ATPase in cerebellum, playing crucial role in maintaining the Na+ and K+ gradients, depend on gender, age, and duration of diabetic impact.

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References

  1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103:137–149

    CAS  Article  PubMed  Google Scholar 

  2. Frazon R, Chiarani F, Mendes RH, Bello-Klein A, Wyse AT (2005) Dietary soy prevents brain Na+,K+-ATPase reduction in streptozotocin diabetic rats. Diabetes Res Clin Pract 69:107–112. doi:10.1016/j.diabres.2004.11.010

    Article  Google Scholar 

  3. Cameron FJ (2015) The impact of diabetes on brain function in childhood and adolescence. Pediatr Clin North Am 62:911–927

    Article  PubMed  Google Scholar 

  4. Brands AM, Henselmans JM, de Haan EH, Biessels GJ (2003) Diabetic encephalopathy: an underexposed complication of diabetes mellitus. Ned Tijdschr Geneeskd 147:11–14

    CAS  PubMed  Google Scholar 

  5. Mijnhout GS, Scheltens P, Diamant M, Biessels GJ, Wessels AM, Simsek S, Snoek FJ, Heine RJ (2006) Diabetic encephalopathy: a concept in need of a definition. Diabetologia 49:1447–1448. doi:10.1007/s00125-006-0221-8

    CAS  Article  PubMed  Google Scholar 

  6. Xie Z, Cai T (2003) Na+-K+-ATPase-mediated signal transduction: from protein interaction to cellular function. Mol Interv 3:157–168

    CAS  Article  PubMed  Google Scholar 

  7. Benarroch EE (2011) Na+,K+-ATPase: functions in the nervous system and involvement in neurologic disease. Neurology 76:287–293. doi:10.1212/WNL.0b013e3182074c2f

    Article  PubMed  Google Scholar 

  8. de Lores Arnaiz GR, Ordieres MG (2014) Brain Na(+),K(+)-ATPase activity in aging and disease. Int J Biomed Sci 10:85–102

    PubMed  PubMed Central  Google Scholar 

  9. Brown PD, Davies SL, Speake T, Millar ID (2004) Molecular mechanisms of cerebrospinal fluid production. Neuroscience 129:957–970. doi:10.1016/j.neuroscience.2004.07.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201. doi:10.1016/j.neuron.2008.01.003

    CAS  Article  PubMed  Google Scholar 

  11. Desfrere L, Karlsson M, Hiyoshi H, Malmersjö S, Nanou E, Estrada M, Miyakawa A, Lagercrantz H, El Manira A, Lal M, Uhlén P (2009) Na,K-ATPase signal transduction triggers CREB activation and dendritic growth. Proc Natl Acad Sci USA 106:2212–2217. doi:10.1073/pnas.0809253106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Jorgensen PL, Pedersen PA (2001) Structure–function relationships of Na+, K+, ATP, or Mg2+ binding and energy transduction in Na,K-ATPase. Biochim Biophys Acta 1505:57–74

    CAS  Article  PubMed  Google Scholar 

  13. Lopez LB, Quintas LE, Noël F (2002) Influence of development on Na(+)/K(+)-ATPase expression: isoform- and tissue-dependency. Comp Biochem Physiol A 131:323–333

    Article  Google Scholar 

  14. Larsen BR, Stoica A, MacAulay N (2016) Managing brain extracellular K(+) during neuronal activity: the physiological role of the Na(+)/K(+)-ATPase subunit isoforms. Front Physiol 22(7):141

    Google Scholar 

  15. Dobretsov M, Stimers JR (2005) Neuronal function and alpha3 isoform of the Na/K-ATPase. Front Biosci 10:2373–2396

    CAS  Article  PubMed  Google Scholar 

  16. Moseley AE, Lieske SP, Wetzel RK, James PF, He S, Shelly DA, Paul RJ, Boivin GP, Witte DP, Ramirez JM, Sweadner KJ, Lingrel JB (2003) The Na,K-ATPase alpha2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice. J Biol Chem 278:5317–5324

    CAS  Article  PubMed  Google Scholar 

  17. Munzer JS, Daly SE, Jewell-Motz EA, Lingrel JB, Blostein R (1994) Tissue- and isoform-specific kinetic behavior of the Na,K-ATPase. J Biol Chem 269:16668–16676

    CAS  PubMed  Google Scholar 

  18. Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:537–546

    CAS  PubMed  Google Scholar 

  19. Stevens MJ, Dananberg J, Feldman EL, Lattimer SA, Kamijo M, Thomas TP, Shindo H, Sima AA, Greene DA (1994) The linked roles of nitric oxide, aldose reductase and (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Investig 94:853–859

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, Schwartz MW (1993) Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Investig 92:1824–1830

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Banks WA (2004) The source of cerebral insulin. Eur J Pharmacol 490:5–12

    CAS  Article  PubMed  Google Scholar 

  22. Pierce GN, Dhalla NS (1983) Sarcolemmal Na+–K+-ATPase activity in diabetic rat heart. Am J Physiol 245:C241–C247

    CAS  PubMed  Google Scholar 

  23. Kato K, Lukas A, Chapman DC, Rupp H, Dhalla NS (2002) Differential effects of etomoxir treatment on cardiac Na+–K+ ATPase subunits in diabetic rats. Mol Cell Biochem 232:57–62

    CAS  Article  PubMed  Google Scholar 

  24. Liu X, Suzuki H, Sethi R, Tappia PS, Takeda N, Dhalla NS (2006) Blockade of the renin–angiotensin system attenuates sarcolemma and sarcoplasmic reticulum remodeling in chronic diabetes. Ann N Y Acad Sci 1084:141–154. doi:10.1196/annals.1372.003

    CAS  Article  PubMed  Google Scholar 

  25. Vlkovicova J, Javorkova V, Stefek M, Kyselova Z, Gajdosikova A, Vrbjar N (2006) Effect of the pyridoindole antioxidant stobadine on the cardiac Na+,K+-ATPase in rats with streptozotocin-induced diabetes. Gen Physiol Biophys 25:111–124

    CAS  PubMed  Google Scholar 

  26. Vér A, Szántó I, Bányász T, Csermely P, Végh E, Somogyi J (1997) Changes in the expression of Na+/K+-ATPase isoenzymes in the left ventricle of diabetic rat hearts: effect of insulin treatment. Diabetologia 40:1255–1262

    Article  PubMed  Google Scholar 

  27. Rosta K, Tulassay E, Enzsoly A, Ronai K, Szantho A, Pandics T, Fekete A, Mandl P, Ver A (2009) Insulin induced translocation of Na+/K+-ATPase is decreased in the heart of streptozotocin diabetic rats. Acta Pharmacol Sin 30:1616–1624. doi:10.1038/aps.2009.162

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Dhalla NS, Takeda N, Rodriguez-Leyva D, Elimban V (2014) Mechanisms of subcellular remodeling in heart failure due to diabetes. Heart Fail Rev 19:87–99

    CAS  Article  PubMed  Google Scholar 

  29. Vér A, Szántó I, Csermely P, Kalff K, Végh E, Bányász T, Marcsek Z, Kovács T, Somogyi J (1995) Effect of streptozotocin-induced diabetes on kidney Na+/K(+)-ATPase. Acta Physiol Hung 83:323–332

    PubMed  Google Scholar 

  30. Javorkova V, Mezesova L, Vlkovicova J, Vrbjar N (2009) Acute diabetes mellitus and its influence on renal Na,K-ATPase in both genders. Gen Physiol Biophys 28:39–46

    CAS  Article  PubMed  Google Scholar 

  31. Javorkova V, Mezesova L, Vlkovicova J, Vrbjar N (2010) Influence of sub-chronic diabetes mellitus on functional properties of renal Na+,K+-ATPase in both genders of rats. Gen Physiol Biophys 29:266–274. doi:10.4149/gpb_2010_03_266

    CAS  Article  PubMed  Google Scholar 

  32. Ver A, Csermely P, Banyasz T, Kovacs T, Somogyi J (1995) Alterations in the properties and isoform ratios of brain Na+/K+-ATPase in streptozotocin diabetic rats. Biochim Biophys Acta 1237:143–150

    Article  PubMed  Google Scholar 

  33. Calgaroto NS, Thomé GR, da Costa P, Baldissareli J, Hussein FA, Schmatz R, Rubin MA, Signor C, Ribeiro DA, Carvalho FB, de Oliveira LS, Pereira LB, Morsch VM, Schetinger MR (2014) Effect of vitamin D3 on behavioural and biochemical parameters in diabetes type 1-induced rats. Cell Biochem Funct 32:502–510. doi:10.1002/cbf.3044

    CAS  Article  PubMed  Google Scholar 

  34. Stefanello N, Schmatz R, Pereira LB, Rubin MA, da Rocha JB, Facco G, Pereira ME, Mazzanti CM, Passamonti S, Rodrigues MV, Carvalho FB, da Rosa MM, Gutierres JM, Cardoso AM, Morsch VM, Schetinger MR (2014) Effects of chlorogenic acid, caffeine, and coffee on behavioral and biochemical parameters of diabetic rats. Mol Cell Biochem 388:277–286. doi:10.1007/s11010-013-1919-9

    CAS  Article  PubMed  Google Scholar 

  35. Yin Z, Yu H, Chen S, Ma C, Ma X, Xu L, Ma QuR, Ma S (2015) Asiaticoside attenuates diabetes induced cognition deficits by regulating PI3K/Akt/NF-κB pathway. Behav Brain Res 292:288–299. doi:10.1016/j.bbr.2015.06.024

    CAS  Article  PubMed  Google Scholar 

  36. Kaločayová B, Mézešová L, Barteková M, Vlkovičová J, Jendruchová V, Vrbjar N (2015) Effect of duration of diabetes mellitus type 1 on properties of Na,K-ATPase in cerebral cortex. Mol Cell Biochem 405:41–52. doi:10.1007/s11010-015-2394-2

    Article  PubMed  Google Scholar 

  37. Sennoune S, Gerbi A, Duran MJ, Grillasca JP, Compe E, Pierre S, Planells R, Bourdeau M, Vague P, Pieroni G, Maixent JM (2000) Effect of streptozotocin-induced diabetes on rat liver Na+/K+-ATPase. Eur J Biochem 267:1–9

    Article  Google Scholar 

  38. Kjeldsen K, Braendgaard H, Sidenius P, Larsen JS, Norgaard A (1987) Diabetes decreases Na+–K+ pump concentration in skeletal muscles, heart ventricular muscle, and peripheral nerves of rat. Diabetes 36:842–848

    CAS  Article  PubMed  Google Scholar 

  39. Leong SF, Leung TK (1991) Diabetes induced by streptozotocin causes reduced Na–K ATPase in the brain. Neurochem Res 16:1161–1165

    CAS  Article  PubMed  Google Scholar 

  40. Zarros A, Liapi C, Galanopoulou P, Marinou K, Mellios Z, Skandali N, Al-Humadi H, Anifantaki F, Gkrouzman E, Tsakiris S (2009) Effects of adult-onset streptozotocin-induced diabetes on the rat brain antioxidant status and the activities of acetylcholinesterase, (Na+,K+)- and Mg2+-ATPase: modulation by Lcysteine. Metab Brain Dis 24:337–348. doi:10.1007/s11011-009-9133-x

    CAS  Article  PubMed  Google Scholar 

  41. Lavaque E, Mayen A, Azcoitia I, Tena-Sempere M, Garcia- Segura LM (2006) Sex differences, developmental changes, response to injury and cAMP regulation of the mRNA levels of steroidogenic acute regulatory protein, cytochrome p450scc, and aromatase in the olivocerebellar system. J Neurobiol 66:308–318

    CAS  Article  PubMed  Google Scholar 

  42. Dean SL, McCarthy MM (2008) Steroids, sex and the cerebellar cortex: implications for human disease. Cerebellum 7(1):38–47

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Mathews WR, DuCharme DW, Hamlyn JM, Harris DW, Mandel F, Clark MA, Ludens JH (1991) Mass spectral characterization of an endogenous digitalis like factor from human plasma. Hypertension 17:930–935

    CAS  Article  PubMed  Google Scholar 

  44. Chen S, Yuan C, Clough D, Haddy FJ, Pamnani MB (1993) Role of digitalis-like substance in experimental insulin-dependent diabetes mellitus hypertension. J Cardiovasc Pharmacol 22:S20–S21

    CAS  Article  PubMed  Google Scholar 

  45. Chen S, Yuan C, Clough D, Schooley J, Haddy FJ, Pamnani MB (1993) Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes in reduced renal mass rats. Am J Hypertens 6:397–406

    CAS  PubMed  Google Scholar 

  46. LaBella FS, Bihler I, Templeton J, Kim RS, Hnatowich M, Rohrer D (1985) Progesterone derivatives that bind to the digitalis receptor: effects on Na+,K+-ATPase and isolated tissues. Fed Proc 44:2806–2811

    CAS  PubMed  Google Scholar 

  47. Jorgensen PL (1974) Purification and characterization of (Na+,K+)-ATPase. III. Purification from the outer medulla of mammalian kidney after selective removal of membrane components by sodium dodecylsulphate. Biochim Biophys Acta 356:36–52

    CAS  Article  PubMed  Google Scholar 

  48. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  49. Taussky HH, Shorr EE (1953) A microcolorimetric method for the determination of inorganic phosphorus. J Biol Chem 202:675–685

    CAS  PubMed  Google Scholar 

  50. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. doi:10.1016/0003-2697(76)90527-3

    CAS  Article  PubMed  Google Scholar 

  51. Seghieri G, Tesi F, Anichini R, De Bellis A, Fabbri G, Malagoli R, Franconi F (2007) Gender modulates the relationship between body weight and plasma glucose in overweight or obese subjects. Diabetes Res Clin Pract 80:134–138. doi:10.1016/j.diabres.2007.10.025

    Article  Google Scholar 

  52. Aaberg ML, Burch DM, Hud ZR, Zacharias MP (2008) Gender differences in the onset of diabetic neuropathy. J Diabetes Complicat 22:83–87. doi:10.1016/j.jdiacomp.2007.06.009

    Article  PubMed  Google Scholar 

  53. Booya F, Bandarian F, Larijani B, Pajouhi M, Nooraei M, Lotfi J (2005) Potential risk factors for diabetic neuropathy: a case control study. BMC Neurol 5:24. doi:10.1186/1471-2377-5-24

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ahmed N, Zahra N (2011) Neurochemical correlates of alloxan diabetes: glucose and related brain metabolism in the rat. Neurochem Res 36:494–505. doi:10.1007/s11064-010-0369-y

    CAS  Article  PubMed  Google Scholar 

  55. Vlkovičová J, Javorková V, Pecháňová O, Vrbjar N (2005) Gender difference in functional properties of Na,K-ATPase in the heart of spontaneously hypertensive rats. Life Sci 76:971–982

    Article  PubMed  Google Scholar 

  56. Peković S, Nedeljković N, Nikezić G, Horvat A, Stojiljković M, Rakić L, Martinović JV (1997) Biochemical characterization of the hippocampal and striatal Na,K-ATPase reveals striking differences in kinetic properties. Gen Physiol Biophys 16:227–240

    PubMed  Google Scholar 

  57. Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138:863–870

    CAS  PubMed  Google Scholar 

  58. Rune GM, Frotscher M (2005) Neurosteroid synthesis in the hippocampus: role in synaptic plasticity. Neuroscience 136:833–842

    CAS  Article  PubMed  Google Scholar 

  59. Alivisatos SG, Deliconstantinos G, Theodosiadis GP (1981) Specificity of binding of cholesterol, steroid hormones and other compounds in synaptosomal plasma membranes, and their effect on ouabain-sensitive ATPase. Biochim Biophys Acta 643:650–658

    CAS  Article  PubMed  Google Scholar 

  60. Farnsworth WE (1990) The prostate plasma membrane as an androgen receptor. Membr Biochem 9:141–162

    CAS  Article  PubMed  Google Scholar 

  61. Zheng J, Ramirez VD (1999) Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na+,K+-ATPase of porcine cortex. Eur J Pharmacol 368:95–102

    CAS  Article  PubMed  Google Scholar 

  62. Blanco G, Mercer RW (1998) Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am J Physiol 275:F633–F650

    CAS  PubMed  Google Scholar 

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Acknowledgements

The study was supported by Slovak Grant Agency: VEGA-2/0141/13. The authors thank to Mrs. Z. Hradecká for her careful technical assistance.

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  1. Institute for Heart Research, Slovak Academy of Sciences, Dúbravska cesta 9, Bratislava, 842 33, Slovak Republic

    B. Kaločayová, L. Mézešová, M. Barteková, J. Vlkovičová, V. Jendruchová & N. Vrbjar

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  1. B. Kaločayová
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  2. L. Mézešová
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  4. J. Vlkovičová
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Correspondence to N. Vrbjar.

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Kaločayová, B., Mézešová, L., Barteková, M. et al. Properties of Na,K-ATPase in cerebellum of male and female rats: effects of acute and prolonged diabetes. Mol Cell Biochem 425, 25–36 (2017). https://doi.org/10.1007/s11010-016-2859-y

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Keywords

  • Sodium pump
  • Gender difference
  • Enzyme kinetics
  • Cerebellum