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The inhibitory effect of copper ions on lymphocyte Kv1.3 potassium channels

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We applied the whole-cell patch-clamp technique to study the inhibitory effect of copper ions (Cu) on the activity of Kv1.3 channels expressed in human lymphocytes. Application of Cu reversibly inhibited the currents to about 10% of the control value in a concentration-dependent manner with the half blocking concentration of 5.28±0.5 µM and the Hill's coefficient of 3.83±0.18. The inhibitory effect was saturated at 10 µM concentration. The inhibition was time-dependent and it was correlated in time with a significant slowing of the current activation rate. In contrast the voltage dependence of activation was not changed by Cu as well as the inativation kinetics. The inhibitory effect of Cu was voltage-independent. It was also unaffected by changing the extracellular pH in the range from 6.4 to 8.4, raising the extracellular potassium concentration to 150 mM and by changing the holding potential from -90 to -60 mV. The inhibitiory effect of Cu was not changed in the presence of an equivalent concentration of Zn. Altogether, obtained data suggest that Cu inhibits Kv1.3 channels by a different mechanism than Zn and that Cu and Zn act on different binding sites. The inhibitory effect of Cu was probably due to a specific binding of Cu on binding sites on the channels. Possible physiological significance of the Cu-induced inhibition of Kv1.3 channels is discussed.
Voltage-gated potassium channels (Kv) are predominating and most widely studied ion channels in T lymphocytes (TL). Patch-clamp studies provide evidence that three different types of Kv channels, termed n, n' and l, are present in human in mouse TL. This review focuses on: 1) studies on biophysical properties of the three channel types, 2) role of Kv channels in TL cell function. Available data demonstrate that the activity of Kv channels in TL is required for: i. setting the TL resting membrane potential, ii. cell mitogenesis, iii. volume regulation. Blockade of Kv channels effectively blocks both mitogenesis and volume regulation of T cells, 3) changes of Kv channel expression in diseases. Results of patch-clamp studies provide evidence that expression of TL Kv channels is significantly altered in autoimmune diseases and in chronic renal failure. Autoimmune diseases are linked to an abnormally high expression of the l type Kv channels, which arises in parallel with the onset of autoimmunity, in mouse double-negative (DN-CD4-CD8-) TL. In chronic renal failure, a significant increase in the whole-cell potassium conductance (gKv), probably also due to altered channel expression, appears in human TL. The rise in the gKv value parallels the onset of the disease. Moreover, long-term therapy of uremic patients with recombinant human Erythropoietin is linked to a significant decrease in the gKv value towards the level of control TL. Altogether, the data demonstrate that patch-clamp studies on the Kv channels may provide a valuable tool delineating the role of the channels in TL cell-function and the pathogenesis of the diseases.
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