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7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

  • Ion channels, receptors and transporters
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Abstract

In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.

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Acknowledgments

This work was supported by Mecenatura (P.H.), TÁMOP-4.2.2.D-15/1/KONV-2015-0016 project (implemented through the New Széchenyi Plan co-financed by the European Social Fund, G.P.), GINOP 2.3.2-15 C122500 to GP, KTIA_NAP_13-2-2015-0009 (Z.V.), Hungarian Scientific Research Fund OTKA NN111006 (L.V.). P.H. is a Lajos Szodoray Fellow and supported by János Bolyai Fellowship. Z.V. is awarded with János Bolyai Fellowship. A.B was cofinanced by Astellas Pharma Fellowship and National Excellence Program. This research was partly realized in the frames of TÁMOP 4.2.4. A/2-11-1-2012-0001 “National Excellence Program – Elaborating and operating an inland student and researcher personal support system convergence program.” The project was subsidized by the European Union and cofinanced by the European Social Fund.

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Authors and Affiliations

  1. Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary

    András Balajthy, Zoltán Pethő & György Panyi

  2. Department of Internal Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary

    Sándor Somodi & György Paragh

  3. Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, H-6726, Szeged, Temesvári Krt. 62., Hungary

    Mária Péter & László Vígh

  4. MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, University of Debrecen, Debrecen, Egyetem tér 1., H-4032, Hungary

    Zoltán Varga

  5. Department of Pediatrics, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary

    Gabriella P. Szabó

  6. Department of Biophysics and Cell Biology, Faculty of Dentistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary

    Péter Hajdu

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  1. András Balajthy
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Balajthy, A., Somodi, S., Pethő, Z. et al. 7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome. Pflugers Arch - Eur J Physiol 468, 1403–1418 (2016). https://doi.org/10.1007/s00424-016-1851-4

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