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Departments of
* Internal Medicine, and
Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, 45267; and
Division of Hematology/Oncology, Cincinnati Children’s Hospital, Cincinnati, OH 45229
T lymphocytes are exposed to hypoxia during their development and
also when they migrate to hypoxic pathological sites such as tumors and
wounds. Although hypoxia can affect T cell development and function,
the mechanisms by which immune cells sense and respond to changes in
O2-availability are poorly understood. K+
channels encoded by the Kv1.3 subtype of the voltage-dependent Kv1 gene
family are highly expressed in lymphocytes and are involved in the
control of membrane potential and cell function. In this study, we
investigate the sensitivity of Kv1.3 channels to hypoxia in freshly
isolated human T lymphocytes and leukemic Jurkat T cells. Acute
exposure to hypoxia (20 mmHg, 2 min) inhibits Kv1.3 currents in both
cell types by 20%. Prolonged exposure to hypoxia (1% O2
for 24 h) selectively decreases Kv1.3 protein levels in Jurkat T
cells by 47%, but not Kv
2 and SK2 Ca-activated K+
channel subunit levels. The decrease in Kv1.3 protein levels occurs
with no change in Kv1.3 mRNA expression and is associated with a
significant decrease in K+ current density. A decrease in
Kv1.3 polypeptide levels similar to that obtained during hypoxia is
produced by Kv1.3 channel blockage. Our results indicate that hypoxia
produces acute and long-term inhibition of Kv1.3 channels in T
lymphocytes. This effect could account for the inhibition of lymphocyte
proliferation during hypoxia. Indeed, we herein present evidence
showing that hypoxia selectively inhibits TCR-mediated proliferation
and that this inhibition is associated with a decrease in Kv1.3
proteins.
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