7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome.
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.
Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
András
A
Balajthy
Department of Internal Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
Sándor
S
Somodi
Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
Zoltán
Z
Pethő
Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, H-6726, Szeged, Temesvári Krt. 62., Hungary.
Mária
M
Péter
MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, University of Debrecen, Debrecen, Egyetem tér 1., H-4032, Hungary.
Zoltán
Z
Varga
Department of Pediatrics, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
Gabriella P
GP
Szabó
Department of Internal Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
György
G
Paragh
Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, H-6726, Szeged, Temesvári Krt. 62., Hungary.
László
L
Vígh
Department of Biophysics and Cell Biology, Faculty of General Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
György
G
Panyi
Department of Biophysics and Cell Biology, Faculty of Dentistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary. hajdup@med.unideb.hu.
Péter
P
Hajdu
D016022:Case-Control Studies; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002648:Child; D003684:Dehydrocholesterols / Q000378:metabolism; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D010641:Phenotype; D019082:Smith-Lemli-Opitz Syndrome / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
D003684:Dehydrocholesterols; D051664:Kv1.3 Potassium Channel; C016705:7-dehydrocholesterol
7-Dehydrocholesterol; Cholesterol; Kv1.3; Smith-Lemli-Opitz syndrome; Voltage-gated ion channel