Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?

Abstract

Membrane receptors and ion transport mechanisms probably have an important role in lymphocyte activation leading to T-lymphocyte proliferation in the immune response. Here we have applied a gigaohm-seal patch clamp technique to reveal the identity and properties of ion channels in human T lymphocytes. A voltage-dependent potassium channel bearing a resemblance to the delayed rectifier of nerve and muscle cells was found to be the predominant ion channel in these cells. In the whole cell recording conformation, the channels open with sigmoid kinetics during depolarizing voltage steps, reaching a maximum K+ conductance of 3-5 nS. The current subsequently becomes almost completely inactivated during a long-lasting depolarization. Currents through single K+ channels recorded in whole cell and outside-out patch recording conformations reveal a unitary channel conductance of about 16 pS in normal Ringer solution. Thus, the peak current corresponds to approximately 200-300 conducting K+ channels per cell. Phytohaemagglutinin (PHA), at concentrations that produce mitogenesis, alters K+ channel gating within 1 min of addition to the bathing solution, causing channels to open more rapidly and at more negative membrane potentials. 3H-thymidine incorporation by T lymphocytes following PHA stimulation is inhibited by the 'classical' K+ channel blockers tetraethylammonium and 4-aminopyridine, and also by quinine, at doses found to block the K+ channel in voltage-clamped T lymphocytes, suggesting that K+ channels may play a part in mitogenesis.

Blockade of Ca2+‐activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

“…With the combined use of patch-clamp electrophysiology and molecular biology, the voltage-dependent K + channel 1.3 (K V 1.3 channel) and the intermediate-conductance Ca 2+ -activated channel (IK channel) (which acquires its Ca 2+ dependency from constitutively bound calmodulin) were found to be the dominating K + -channel types expressed in T cells [5][6][7]. The role of K + channels in the activation of T cells is pivotal, since opening of these channels makes the membrane potential become more negative inside, which in turn increases the influx of Ca 2+ via Ca 2+ -release-activated Ca 2+ channels (CRAC channels) [1,8].…”

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

“…The voltage‐gated K + channel Kv1.3 was first discovered in human T‐cells in 19841 and has since then been pursued as a target for immunosuppression. After the channel was cloned, the pharmaceutical industry initiated Kv1.3 discovery programs in the mid‐1990s but largely failed to identify compounds that were suitable for development 2.…”

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

“…S5 and S6 segments with the pore loop between them form the pore domain (PD) of the channel which includes the ion conducting pore, whereas S1-S4 and the positively charged amino acids in S4 make up the voltage-sensing domain (VSD). Kv1.3, which belongs to the Shaker subfamily of Kv channels, is the predominant voltage-gated K + channel of human T lymphocytes [18,39].The main function of Kv1.3 channels during T cell activation is the maintenance of a permissive membrane potential (approximately equal to −50 mV) required for appropriate extracellular Ca 2+ entry and proper Ca 2+ signaling. By the use of Kv1.3-selective antagonists, lymphocyte proliferation and IL-2 production can be inhibited [14,47].…”