Abstract
Evidence accumulating during almost 50 years suggests Na+, K+-ATPase dysfunction in bipolar disorder, a disease treatable with chronic administration of lithium salts, carbamazepine or valproic acid. Three Na+, K+-ATPase α subunits (α1–3) and two β subunits (β1 and β2) are expressed in brain together with the auxiliary protein FXYD7. FXYD7 decreases K+ affinity, and thus contributes to stimulation of the enzyme at elevated extracellular K+ concentrations. Na+, K+-ATPase subtype and FXYD7 genes were determined by RT-PCR in mice co-expressing one fluorescent signal with an astrocytic marker or a different fluorescent signal with a neuronal marker and treated for 14 days with carbamazepine. Following fluorescence-activated cell sorting of neurons and astrocytes it was shown that α2 Expression was upregulated in astrocytes and neurons and α1 selectively in neurons, but α3 was unchanged. β1 was upregulated in astrocytes, but not in neurons. β2 was unaffected in astrocytes and absent in neurons. FXYD7 was downregulated specifically in neurons. According to cited literature data these changes should facilitate K+ uptake in neurons, without compromising preferential uptake in astrocytes at increased extracellular K+ concentrations. This process seems to be important for K+ homeostasis of the cellular level of the brain (Xu et al. Neurochem Res E-pub Dec. 12, 2012).
Similar content being viewed by others
References
Skou JC, Esmann M (1992) The Na, K-ATPase. J Bioenerg Biomembr 24:249–261
Kaplan JH (2002) Biochemistry of Na, K-ATPase. Annu Rev Biochem 71:511–535
Lecuona E, Luquín S, Avila J, García-Segura LM, Martín-Vasallo P (1996) Expression of the beta 1 and beta 2(AMOG) subunits of the Na, K-ATPase in neural tissues: cellular and developmental distribution patterns. Brain Res Bull 40:167–174
McGrail KM, Phillips JM, Sweadner KJ (1991) Immunofluorescent localization of three Na, K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na, K-ATPase. J Neurosci 11:381–391
Tipsmark CK (2008) Identification of FXYD protein genes in a teleost: tissue-specific expression and response to salinity change. Am J Physiol Regul Integr Comp Physiol 294:R1367–R1378
Béguin P, Crambert G, Monnet-Tschudi F, Uldry M, Horisberger JD, Garty H, Geering K (2002) FXYD7 is a brain-specific regulator of Na, K-ATPase alpha 1-beta isozymes. EMBO J 21:3264–3273
Coppen A, Shaw DM, Malleson A, Costain R (1966) Mineral metabolism in mania. Br Med J 1:71–75
Shaw DM (1966) Mineral metabolism, mania, and melancholia. Br Med J 2:262–267
Goldstein I, Levy T, Galili D, Ovadia H, Yirmiya R, Rosen H, Lichtstein D (2006) Involvement of Na(+), K(+)-ATPase and endogenous digitalis-like compounds in depressive disorders. Biol Psychiatry 60:491–499
Rose AM, Mellett BJ, Valdes R Jr, Kleinman JE, Herman MM, Li R, el-Mallakh RS (1998) Alpha 2 isoform of the Na, K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals. Biol Psychiatry 44:892–897
Lichtstein D, Minc D, Bourrit A, Deutsch J, Karlish SJ, Belmaker H, Rimon R, Palo J (1985) Evidence for the presence of ‘ouabain like’ compound in human cerebrospinal fluid. Brain Res 325:13–19
Huff MO, Li XP, Ginns E, El-Mallakh RS (2010) Effect of ethacrynic acid on the sodium- and potassium-activated adenosine triphosphatase activity and expression in old order amish bipolar individuals. J Affect Disord 123:303–307
Mynett-Johnson L, Murphy V, McCormack J, Shields DC, Claffey E, Manley P, McKeon P (1998) Evidence for an allelic association between bipolar disorder and a Na+, K+ adenosine triphosphatase alpha subunit gene (ATP1A3). Biol Psychiatry 44:47–51
Banerjee U, Dasgupta A, Rout JK, Singh OP (2012) Effects of lithium therapy on Na+-K+-ATPase activity and lipid peroxidation in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 37:56–61
Post RM (1990) Anticonvulsants for the lithium-resistant bipolar patient. In: Amsterdam J (ed) Pharmacology of depression: application for the outpatient practioner. Marcel Dekker, New York, pp 129–158
Post RM, Weiss SRB, Chuang DM, Ketter TA (1994) Mechanisms of action of carbamazepine in seizure and affective disorders. In: Joffe RJ, Calabrese JR (eds) Anticonvulsants in psychiatry. Marcel Dekker, New York, pp 43–92
Dias VV, Balanzá-Martinez V, Soeiro-de-Souza MG, Moreno RA, Figueira ML, Machado-Vieira R, Vieta E (2012) Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview. Acta Psychiatr Scand 126:315–331
Chen CH, Lin SK (2012) Carbamazepine treatment of bipolar disorder: a retrospective evaluation of naturalistic long-term outcomes. BMC Psychiatry 12:47
Song D, Li B, Yan E, Man Y, Wolfson M, Chen Y, Peng L (2012) Chronic treatment with anti-bipolar drugs causes intracellular alkalinization in astrocytes, altering their functions. Neurochem Res 37:2524–2540
Hamakawa H, Murashita J, Yamada N, Inubushi T, Kato N, Kato T (2004) Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder. Psychiatry Clin Neurosci 58:82–88
Deigweiher K, Koschnick N, Pörtner HO, Lucassen M (2008) Acclimation of ion regulatory capacities in gills of marine fish under environmental hypercapnia. Am J Physiol Regul Integr Comp Physiol 295:R1660–R1670
Fu H, Li B, Hertz L, Peng L (2012) Contributions in astrocytes of SMIT1/2 and HMIT to myo-inositol uptake at different concentrations and pH. Neurochem Int 61:187–194
Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW, Sanes JR (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28:41–51
Seki M, Nawa H, Morioka T, Fukuchi T, Oite T, Abe H, Takei N (2002) Establishment of a novel enzyme-linked immunosorbent assay for Thy-1; quantitative assessment of neuronal degeneration. Neurosci Lett 329:185–188
Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH, Han X, Takano T, Wang S, Sim FJ, Goldman SA, Nedergaard M (2007) The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J Neurosci 27:12255–12266
Li B, Hertz L, Peng L (2012) Aralar mRNA and protein levels in neurons and astrocytes freshly isolated from young and adult mouse brain and in maturing cultured astrocytes. Neurochem Int 61:1325–1332
Kong EK, Peng L, Chen Y, Yu AC, Hertz L (2002) Up-regulation of 5-HT2B receptor density and receptor-mediated glycogenolysis in mouse astrocytes by long-term fluoxetine administration. Neurochem Res 27:113–120
Rajasekaran SA, Gopal J, Willis D, Espineda C, Twiss JL, Rajasekaran AK (2004) Na, K-ATPase β1 subunit increase the translation efficiency of the α1 subunit in MSV-MDCK cells. Mol Biol Cell 15:3224–3232
Tumlin JA, Hoban CA, Medford RM, Sands JM (1994) Expression of Na-K-ATPase alpha- and beta- subunit mRNA and protein isoform in the rat nephron. Am J Physiol 266:240–245
Summa V, Camargo SM, Bauch C, Zecevic M, Verrey F (2004) Isoform specificity of human Na, K-ATPase localization and aldosterone regulation in mouse kidney cells. J Physiol 555:355–364
Murphy KT, Macdonald WA, McKenna MJ, Clausen T (2006) Ionic mechanisms of excitation-induced regulation of Na+-K+-ATPase mRNA expression in isolated rat EDL muscle. Am J Physiol Regul Integr Comp Physiol 290:R1397–R1406
Stengelin MK, Hoffman JF (1997) Na, K-ATPase subunit isoforms in human reticulocytes: evidence from reverse transcription-PCR for the presence of alpha1, alpha3, beta2, beta3, and gamma. Proc Natl Acad Sci U S A 94:5943–5948
Garcia-Rudaz C, Deng V, Matagne V, Ronnekleiv OK, Bosch M, Han V, Percy AK, Ojeda SR (2009) FXYD1, a modulator of Na, K-ATPase activity, facilitates female sexual development by maintaining gonadotrophin-releasing hormone neuronal excitability. J Neuroendocrinol 21:108–122
El Marjou M, Montalescot V, Buzyn A, Geny B (2000) Modifications in phospholipase D activity and isoform expression occur upon maturation and differentiation in vivo and in vitro in human myeloid cells. Leukemia 14:2118–2127
Peng L, Martin-Vasallo P, Sweadner KJ (1997) Isoforms of Na, K-ATPase alpha and beta subunits in the rat cerebellum and in granule cell cultures. J Neurosci 17:3488–3502
Cameron R, Klein L, Shyjan AW, Rakic P, Levenson R (1994) Neurons and astroglia express distinct subsets of Na, K-ATPase alpha and beta subunits. Brain Res Mol Brain Res 21:333–343
Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278
Hertz L, Lovatt D, Goldman SA, Nedergaard M (2010) Adrenoceptors in brain: cellular gene expression and effects on astrocytic metabolism and [Ca(2+)]i. Neurochem Int 57:411–420
Vladimirova NM, Sautkina EN, Murav’eva TI, Ovchinnikova TV, Potapenko NA (2003) Structural peculiarities of Na+, K+-ATPase isozymes from the calf brain. Bioorg Khim 29:146–158
Peng LA, Juurlink BH, Hertz L (1991) Differences in transmitter release, morphology, and ischemia-induced cell injury between cerebellar granule cell cultures developing in the presence and in the absence of a depolarizing potassium concentration. Brain Res Dev Brain Res 63:1–12
Hertz L (1965) Possible role of neuroglia: a potassium-mediated neuronal–neuroglial–neuronal impulse transmission system. Nature 206:1091–1094
Ballanyi K, Grafe P, ten Bruggencate G (1987) Ion activities and potassium uptake mechanisms of glial cells in guinea-pig olfactory cortex slices. J Physiol 382:159–174
Bender AS, Schousboe A, Reichelt W, Norenberg MD (1998) Ionic mechanisms in glutamate-induced astrocyte swelling: role of K+ influx. J Neurosci Res 52:307–321
Walz W (2000) Role of astrocytes in the clearance of excess extracellular potassium. Neurochem Int 36:291–300
Macaulay N, Zeuthen T (2012) Glial K+ clearance and cell swelling: key roles for cotransporters and pumps. Neurochem Res 37:2299–2309
Wang F, Smith NA, Xu Q, Fujita T, Baba A, Matsuda T, Takano T, Bekar L, Nedergaard M (2012) Astrocytes modulate neural network activity by Ca2+-dependent uptake of extracellular K+. Sci Signal 5:ra26
Bay V, Butt AM (2012) Relationship between glial potassium regulation and axon excitability: a role for glial Kir4.1 channels. Glia 60:651–660
Philibert RA, Cheung D, Welsh N, Damschroder-Williams P, Thiel B, Ginns EI, Gershenfeld HK (2001) Absence of a significant linkage between Na(+), K(+)-ATPase subunit (ATP1A3 and ATP1B3) genotypes and bipolar affective disorder in the old-order Amish. Am J Med Genet 105:291–294
Kirshenbaum GS, Clapcote SJ, Duffy S, Burgess CR, Petersen J, Jarowek KJ, Yücel YH, Cortez MA, Snead OC 3rd, Vilsen B, Peever JH, Ralph MR, Roder JC (2011) Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+, K+-ATPase α3 sodium pump. Proc Natl Acad Sci U S A 108:18144–18149
Goldstein I, Lerer E, Laiba E, Mallet J, Mujaheed M, Laurent C, Rosen H, Ebstein RP, Lichtstein D (2009) Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders. Biol Psychiatry 65:985–991
Crambert G, Hasler U, Beggah AT, Yu C, Modyanov NN, Horisberger JD, Lelièvre L, Geering K (2000) Transport and pharmacological properties of nine different human Na, K-ATPase isozymes. J Biol Chem 275:1976–1986
Horvat A, Momić T, Petrović S, Nikezić G, Demajo M (2006) Selective inhibition of brain Na, K-ATPase by drugs. Physiol Res 55:325–338
Wood AJ, Elphick M, Grahame-Smith DG (1989) Effect of lithium and of other drugs used in the treatment of manic illness on the cation-transporting properties of Na+, K+-ATPase in mouse brain synaptosomes. J Neurochem 52:1042–1049
Grafe P, Reddy MM, Emmert H, ten Bruggencate G (1983) Effects of lithium on electrical activity and potassium ion distribution in the vertebrate central nervous system. Brain Res 279:65–76
Walz W, Hertz E, Hertz L (1983) Lithium-potassium interaction in acutely treated cortical neurons and astrocytes. Prog Neuropsychopharmacol Biol Psychiatry 7:697–702
Walz W, Hertz L (1982) Acute and chronic effects of lithium in therapeutically relevant concentrations on potassium uptake into astrocytes. Psychopharmacology 78:309–313
Acknowledgments
This study was supported by Grants No. 30770667 and 31171036 to LP and No. 31000479 to BL from the National Natural Science Foundation of China.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Li, B., Hertz, L. & Peng, L. Cell-Specific mRNA Alterations in Na+, K+-ATPase α and β Isoforms and FXYD in Mice Treated Chronically with Carbamazepine, an Anti-Bipolar Drug. Neurochem Res 38, 834–841 (2013). https://doi.org/10.1007/s11064-013-0986-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-013-0986-3