Na,K-ATPase alpha isoforms at the blood-cerebrospinal fluid-trigeminal nerve and blood-retina interfaces in the rat

Fluids and Barriers of the CNS

Michael G Harrington²  Dan Levy¹  Brian Armstrong³  Alfred N Fonteh²  Linus Kuo²  Jiarong Chiang²  Matthew Techy²  Paige McCleary²  Xianghong Arakaki² 

[1] Headache Research Laboratory, Department of Anesthesia and Critical Care, Harvard Medical School, 330 Brookline Ave E/CLS 639, Boston, MA, 02115, USA;Molecular Neurology Program, Huntington Medical Research Institutes, 99 N. El Molino Avenue, Pasadena, CA, 91101, USA;Light Microscopy Core Facility, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA

关键词: Retina;    Meninges;    Choroid plexus (CP);    Cerebrospinal fluid (CSF);   

Others  :  806716
DOI  :  10.1186/2045-8118-10-14

 received in 2012-10-20, accepted in 2013-03-07,  发布年份 2013

【 摘 要 】

Background

Cerebrospinal fluid (CSF) sodium concentration increases during migraine attacks, and both CSF and vitreous humor sodium increase in the rat migraine model. The Na,K-ATPase is a probable source of these sodium fluxes. Since Na,K-ATPase isoforms have different locations and physiological roles, our objective was to establish which alpha isoforms are present at sites where sodium homeostasis is disrupted.

Methods

Specific Na,K-ATPase alpha isoforms were identified in rat tissues by immunohistochemistry at the blood-CSF barrier at the choroid plexus, at the blood-CSF-trigeminal barrier at the meninges, at the blood-retina barrier, and at the blood-aqueous barrier at the ciliary body. Calcitonin gene-related peptide (CGRP), occludin, or von Willibrand factor (vWF) were co-localized with Na,K-ATPase to identify trigeminal nociceptor fibers, tight junctions, and capillary endothelial cells respectively.

Results

The Na,K-ATPase alpha-2 isoform is located on capillaries and intensely at nociceptive trigeminal nerve fibers at the meningeal blood-CSF-trigeminal barrier. Alpha-1 and −3 are lightly expressed on the trigeminal nerve fibers but not at capillaries. Alpha-2 is expressed at the blood-retina barriers and, with alpha-1, at the ciliary body blood aqueous barrier. Intense apical membrane alpha-1 was associated with moderate cytoplasmic alpha-2 expression at the choroid plexus blood-CSF barrier.

Conclusion

Na,K-ATPase alpha isoforms are present at the meningeal, choroid plexus, and retinal barriers. Alpha-2 predominates at the capillary endothelial cells in the meninges and retinal ganglion cell layer.

【 授权许可】

   
2013 Arakaki et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

【 参考文献 】

• [1]Hodgkin AL: The Ionic Basis of Nervous Conduction. Science 1964, 145:1148-1154.
• [2]Hodgkin AL, Katz B: The effect of sodium ions on the electrical activity of giant axon of the squid. J Physiol 1949, 108(1):37-77.
• [3]Harrington MG, Fonteh AN, Cowan RP, Perrine K, Pogoda JM, Biringer RG, Huhmer AF: Cerebrospinal fluid sodium increases in migraine. Headache 2006, 46(7):1128-1135.
• [4]Harrington MG, Chekmenev EY, Schepkin V, Fonteh AN, Arakaki X: Sodium MRI in a rat migraine model and a NEURON simulation study support a role for sodium in migraine. Cephalalgia 2011, 31(12):1254-1265.
• [5]Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R: A neural mechanism for exacerbation of headache by light. Nat Neurosci 2010, 13(2):239-245.
• [6]Arakaki X, Foster H, Su L, Do H, Wain AJ, Fonteh AN, Zhou F, Harrington MG: Extracellular sodium modulates the excitability of cultured hippocampal pyramidal cells. Brain Res 2011, 1401:85-94.
• [7]Harrington MG, Fonteh AN, Arakaki X, Cowan RP, Ecke LE, Foster H, Huhmer AF, Biringer RG: Capillary endothelial Na(+), K(+), ATPase transporter homeostasis and a new theory for migraine pathophysiology. Headache 2010, 50(3):459-478.
• [8]Reese TS, Feder N, Brightman MW: Electron microscopic study of the blood–brain and blood-cerebrospinal fluid barriers with microperoxidase. J Neuropathol Exp Neurol 1971, 30(1):137-138.
• [9]Brightman MW, Reese TS: Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 1969, 40(3):648-677.
• [10]Feschenko MS, Donnet C, Wetzel RK, Asinovski NK, Jones LR, Sweadner KJ: Phospholemman, a single-span membrane protein, is an accessory protein of Na, K-ATPase in cerebellum and choroid plexus. J Neurosci 2003, 23(6):2161-2169.
• [11]Masseguin C, LePanse S, Corman B, Verbavatz JM, Gabrion J: Aging affects choroidal proteins involved in CSF production in Sprague–Dawley rats. Neurobiol Aging 2005, 26(6):917-927.
• [12]Keep RF, Xiang J, Ulanski LJ, Brosius FC, Betz AL: Choroid plexus ion transporter expression and cerebrospinal fluid secretion. Acta Neurochir Suppl 1997, 70:279-281.
• [13]Lee HJ, Park HJ, Lee S, Kim YH, Choi I: The sodium-driven chloride/bicarbonate exchanger NDCBE in rat brain is upregulated by chronic metabolic acidosis. Brain Res 2011, 1377:13-20.
• [14]Praetorius J, Nielsen S: Distribution of sodium transporters and aquaporin-1 in the human choroid plexus. Am J Physiol Cell Physiol 2006, 291(1):C59-C67.
• [15]Nabeshima S, Reese TS, Landis DM, Brightman MW: Junctions in the meninges and marginal glia. J Comp Neurol 1975, 164(2):127-169.
• [16]Weerasuriya A, Mizisin AP: The blood-nerve barrier: structure and functional significance. Methods Mol Biol 2011, 686:149-173.
• [17]Dunn JS, Wyburn GM: The anatomy of the blood brain barrier: a review. Scott Med J 1972, 17(1):21-36.
• [18]Vinores SA, McGehee R, Lee A, Gadegbeku C, Campochiaro PA: Ultrastructural localization of blood-retinal barrier breakdown in diabetic and galactosemic rats. J Histochem Cytochem 1990, 38(9):1341-1352.
• [19]Chan-Ling T: The blood retinal interface: similarities and contrasts with the blood–brain interface. In Blood–brain Interfaces: From Ontogeny to Artificial Barriers. Edited by Dermietzel DCS R, Nedergaard M. Weinham: 2006 WILEY-VCH Verlag GmbH & Co; 2006:701-724.
• [20]Noske W, Stamm CC, Hirsch M: Tight junctions of the human ciliary epithelium: regional morphology and implications on transepithelial resistance. Exp Eye Res 1994, 59(2):141-149.
• [21]Wetzel RK, Sweadner KJ: Immunocytochemical localization of NaK-ATPase isoforms in the rat and mouse ocular ciliary epithelium. Invest Ophthalmol Vis Sci 2001, 42(3):763-769.
• [22]Paxinos G: WC: The rat brain in stereotaxic coordinates. 6th edition. London, UK: Academic Press; 2007.
• [23]McGrail KM, Sweadner KJ: Complex Expression Patterns for Na+, K + −ATPase Isoforms in Retina and Optic Nerve. Eur J Neurosci 1990, 2(2):170-176.
• [24]Strassman AM, Weissner W, Williams M, Ali S, Levy D: Axon diameters and intradural trajectories of the dural innervation in the rat. J Comp Neurol 2004, 473(3):364-376.
• [25]Messlinger K, Lennerz JK, Eberhardt M, Fischer MJ: CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation. Headache 2012, 52(9):1411-1427.
• [26]Yang Y, Dai M, Wilson TM, Omelchenko I, Klimek JE, Wilmarth PA, David LL, Nuttall AL, Gillespie PG, Shi X: Na+/K + −ATPase alpha1 identified as an abundant protein in the blood-labyrinth barrier that plays an essential role in the barrier integrity. PLoS One 2011, 6(1):e16547.
• [27]Lucchesi PA, Sweadner KJ: Postnatal changes in Na, K-ATPase isoform expression in rat cardiac ventricle. Conservation of biphasic ouabain affinity. J Biol Chem 1991, 266(14):9327-9331.
• [28]Jacobs BE, Liu Y, Pulina MV, Golovina VA, Hamlyn JM: Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. Am J Physiol Heart Circ Physiol 2012, 302(6):H1317-H1329.
• [29]Hauck C, Potter T, Bartz M, Wittwer T, Wahlers T, Mehlhorn U, Scheiner-Bobis G, McDonough AA, Bloch W, Schwinger RH: Isoform specificity of cardiac glycosides binding to human Na+, K + −ATPase alpha1beta1, alpha2beta1 and alpha3beta1. Eur J Pharmacol 2009, 622(1–3):7-14.
• [30]Amin MS, Reza E, Wang H, Leenen FH: Sodium transport in the choroid plexus and salt-sensitive hypertension. Hypertension 2009, 54(4):860-867.
• [31]Zlokovic BV, Mackic JB, Wang L, McComb JG, McDonough A: Differential expression of Na, K-ATPase alpha and beta subunit isoforms at the blood–brain barrier and the choroid plexus. J Biol Chem 1993, 268(11):8019-8025.
• [32]Fisone G, Snyder GL, Aperia A, Greengard P: Na+, K(+)-ATPase phosphorylation in the choroid plexus: synergistic regulation by serotonin/protein kinase C and isoproterenol/cAMP-PK/PP-1 pathways. Mol Med 1998, 4(4):258-265.
• [33]Ellis DZ, Nathanson JA, Sweadner KJ: Carbachol inhibits Na(+)-K(+)-ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway. Am J Physiol Cell Physiol 2000, 279(6):C1685-C1693.
• [34]Ellis DZ, Nathanson JA, Rabe J, Sweadner KJ: Carbachol and nitric oxide inhibition of Na, K-ATPase activity in bovine ciliary processes. Invest Ophthalmol Vis Sci 2001, 42(11):2625-2631.
• [35]Hou Y, Delamere NA: Influence of ANG II on cytoplasmic sodium in cultured rabbit nonpigmented ciliary epithelium. Am J Physiol Cell Physiol 2002, 283(2):C552-C559.
• [36]Yadav UC, Srivastava SK, Ramana KV: Inhibition of aldose reductase attenuates endotoxin signals in human non-pigmented ciliary epithelial cells. Exp Eye Res 2010, 90(5):555-563.
• [37]Ghosh S, Hernando N, Martin-Alonso JM, Martin-Vasallo P, Coca-Prados M: Expression of multiple Na+, K(+)-ATPase genes reveals a gradient of isoforms along the nonpigmented ciliary epithelium: functional implications in aqueous humor secretion. J Cell Physiol 1991, 149(2):184-194.
• [38]Archer DB: Intraretinal, preretinal, and subretinal new vessels. Trans Ophthalmol Soc U K 1977, 97(4):449-456.
• [39]Marrs JA, Andersson-Fisone C, Jeong MC, Cohen-Gould L, Zurzolo C, Nabi IR, Rodriguez-Boulan E, Nelson WJ: Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules. J Cell Biol 1995, 129(2):507-519.
• [40]Okami T, Yamamoto A, Omori K, Takada T, Uyama M, Tashiro Y: Immunocytochemical localization of Na+, K(+)-ATPase in rat retinal pigment epithelial cells. J Histochem Cytochem 1990, 38(9):1267-1275.
• [41]Ruiz A, Bhat SP, Bok D: Expression and synthesis of the Na, K-ATPase beta 2 subunit in human retinal pigment epithelium. Gene 1996, 176(1–2):237-242.
• [42]Catanzaro O, Labal E, Andornino A, Capponi JA, Di Martino I, Sirois P: Blockade of early and late retinal biochemical alterations associated with diabetes development by the selective bradykinin B1 receptor antagonist R-954. Peptides 2012, 34(2):349-352.
• [43]Di Leo MA, Santini SA, Cercone S, Lepore D, Gentiloni Silveri N, Caputo S, Greco AV, Giardina B, Franconi F, Ghirlanda G: Chronic taurine supplementation ameliorates oxidative stress and Na + K + ATPase impairment in the retina of diabetic rats. Amino Acids 2002, 23(4):401-406.
• [44]McGrail KM, Sweadner KJ: Immunofluorescent localization of two different Na, K-ATPases in the rat retina and in identified dissociated retinal cells. J Neurosci 1986, 6(5):1272-1283.