Abstract
Activation of resting T cells relies on sustained Ca2+ influx across the plasma membrane, which in turn depends on the functional expression of potassium channels, whose activity repolarizes the membrane potential. Depending on the T-cells subset, upon activation the expression of Ca2+- or voltage-activated K+ channels, KCa or Kv, is up-regulated. In this study, by means of patch-clamp technique in the whole cell mode, we have studied in detail the characteristics of Kv and KCa currents in resting and activated human T cells, the only well explored human T-leukemic cell line Jurkat, and two additional human leukemic T cell lines, CEM and MOLT-3. Voltage dependence of activation and inactivation of Kv1.3 current were shifted up to by 15 mV to more negative potentials upon a prolonged incubation in the whole cell mode and displayed little difference at a stable state in all cell lines but CEM, where the activation curve was biphasic, with a high and low potential components. In Jurkat, KCa currents were dominated by apamine-sensitive KCa2.2 channels, whereas only KCa3.1 current was detected in healthy T and leukemic CEM and MOLT-3 cells. Despite a high proliferation potential of Jurkat cells, Kv and KCa currents were unexpectedly small, more than 10-fold lesser as compared to activated healthy human T cells, CEM and MOLT-3, which displayed characteristic Kv1.3high:KCa3.1high phenotype. Our results suggest that Jurkat cells represent perhaps a singular case and call for more extensive studies on primary leukemic T cell lines as well as a verification of the therapeutic potential of specific KCa3.1 blockers to combat acute lymphoblastic T leukemias.
Highlights
Ion channels are pore-forming proteins that mediate transport of ions across biological membranes
All cell lines used in this study were derived from the peripheral blood of patients diagnosed with acute lymphoblastic T leukemia (T-ALL): Jurkat cell line was established from 14-year-old boy in first relapse in 1976; MOLT-3 cell line from 19-year-old man in relapse in 1971; CCRF-CEM cell line from 3-year-old Caucasian girl in relapse in 1964
Kv1.3 is the only member of the family of voltage-dependent Kv channels known to be expressed in healthy human T cells and Jurkat cell line (Cahalan and Chandy, 2009)
Summary
Ion channels are pore-forming proteins that mediate transport of ions across biological membranes. A cell of any type is characterized by a specific pattern of ion channels differentially expressed at various physiologic conditions and organized in precisely regulated functional network. Potassium (K+)-selective channels are key elements involved in control of membrane. Potassium Channels Activity in T-Leukemias potential, cell volume regulation, and shaping of Ca2+ signal (extensively reviewed by Cahalan and Chandy, 2009; Feske et al, 2012). In T cell biology, the most-studied event is activation of naïve or memory T cells through TCR/CD3 complex, leading to proliferation, clone expansion and differentiation into effector T cells. It was estimated that 75% of all genes upregulated during antigen activation in T cells are dependent on Ca2+ influx (Feske et al, 2001)
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