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CELLULAR |
1 Department of Internal Medicine
2 Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267, USA
3 Division of Molecular Immunology
4 Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45267, USA
5 Department of Environmental Health, University of Pittsburgh, PA 15260, USA
T lymphocytes encounter hypoxia when they migrate to pathological sites such as tumours and wounds. The inability of T cells to provide an efficient defence at these sites can in part be explained by the hypoxic environment. Kv1.3 channels, important components of the T cell activation process are inhibited by hypoxia and their inhibition accounts for a hypoxia-induced decrease in T cell proliferation. Although Kv1.3 channels play a key role in T cell O2 sensing, the signalling mechanisms mediating their response to hypoxia are still not understood. In this study, we show that the src-protein tyrosine kinase p56Lck (Lck) is required for Kv1.3 channel response to hypoxia. Pre-exposure to the src inhibitor PP2 abolished the hypoxia-induced inhibition of Kv1.3 channels in primary human T lymphocytes. Moreover, Kv1.3 channel sensitivity to hypoxia was lost in Lck-deficient Jurkat T cells. Further studies with recombinant Kv1.3 channels showed that Kv1.3 channels lack intrinsic O2 sensitivity, but delivery of Lck into the cells and transfection of a constitutively active Lck (Y505FLck) restored their sensitivity to hypoxia. Although Lck is necessary for the Kv1.3 channel response to hypoxia, it does not directly inhibit Kv1.3 channels. Indeed, under normal oxygen tension, delivery of active Lck into L929 cells and overexpression of Y505FLck did not decrease recombinant Kv1.3 currents. On the contrary, activation of endogenous src kinases increased wild-type Kv1.3 currents in T lymphocytes. Our findings indicate that Lck is required for the acute response to hypoxia of human T lymphocytes as it is necessary to confer O2 sensitivity on Kv1.3 channels.
(Received 17 March 2006;
accepted after revision 3 April 2006;
first published online 6 April 2006)
Corresponding author L. Conforti: Department of Internal Medicine, 231 Albert Sabin Way, University of Cincinnati, Cincinnati, OH 45267-0585, USA. Email: laura.conforti{at}uc.edu
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