Voltage-gated potassium channels are required for human T lymphocyte activation.

Abstract

The calcium channel blockers, verapamil and diltiazem, inhibit phytohemagglutinin (PHA)-induced mitogenesis at concentrations that block the T lymphocyte K channel currents. K channel blockers also inhibit the allogeneic mixed lymphocyte response in a dose-dependent manner with the same potency sequence as for block of K currents. K channel blockers inhibit PHA-stimulated mitogenesis only if added during the first 20-30 h after PHA addition, but not later, indicating a requirement for functional K channels during this period. We investigated the effect of K channel blockers on various aspects of protein synthesis for two reasons: first, protein synthesis appears to be necessary for the events leading to DNA synthesis, and second, the increase in the protein synthetic rate commences during the first 24-48 h after PHA addition. PHA-induced total protein synthesis was reduced to the level in unstimulated T lymphocytes by K channel blockers in a dose-dependent manner with the same potency sequence as for the block of K currents and inhibition of [3H]thymidine incorporation. Two-dimensional gel electrophoresis demonstrated that although the synthesis of the majority of proteins was reduced by K channel blockers to the level in unstimulated T cells, some proteins continued to be synthesized at an enhanced rate compared with resting cells. Two proteins, S and T, detected by two-dimensional gel electrophoresis in unstimulated T lymphocytes, appeared to be reduced in intensity in gels of PHA-treated T lymphocytes, in contrast to the increased synthesis of the remaining proteins. 4-Aminopyridine (4-AP), at concentrations that inhibit protein synthesis, prevented the apparent PHA-induced reduction of proteins S and T. These proteins may play a role in maintaining the T lymphocyte in a resting state and may be related to the translation inhibitory factors reported to be present at a higher specific activity in quiescent T lymphocytes than in PHA-activated T cells. The expression of the IL-2 receptor (Tac) during T lymphocyte activation was not altered by K channel blockers, whereas the production of interleukin 2 (IL-2) was reduced to the level in unstimulated T lymphocytes. Exogenous IL-2 partially relieved the inhibition of mitogenesis by low, but not by high, concentrations of 4-AP. These experiments clarify the role of K channels in T lymphocyte activation and suggest that functional K channels are required either for protein synthesis or for events leading to protein synthesis.

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

“…However, the astonishing aspect of our study was that nimodipine specifically induced apoptosis in microglia and that this effect was mediated via a mechanism that could not be linked to the blockade of calcium channels, which we expected to be the primary target of nimodipine. The observed effects also could not be linked to unspecific blockage of potassium channels (26,27,33,34). Whether microglia express Ca v channels is still a matter of debate (35).…”

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

“…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]. It has been reported earlier by several labs that CHOL is a significant regulator of various types of ion channels including Kv1.3 [27,49,52].…”

K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity

“…During activation, inositol 1,4,5-triphosphate generation induces the release of Ca 2ϩ from internal stores. Depletion of these Ca 2ϩ stores causes calcium-release-activated calcium (CRAC) 3 channels to open in the membrane, and the resulting Ca 2ϩ influx sustains elevated levels of cytosolic Ca 2ϩ (8 -11). Ca 2ϩ influx through CRAC channels is reduced at depolarized potentials, and consequently, membrane depolarization attenuates the Ca 2ϩ signal (10 -13).…”

“…ϩ channels in T lymphocytes, the voltage-gated Kv1.3 channel (also known as KCNA3 (HUGO nomenclature)) and the Ca 2ϩ -activated IKCa1 channel (also known as KCNN4 (HUGO nomenclature); K Ca 3.1 (International Union of Pharmacology nomenclature) (1)), regulate Ca 2ϩ signaling by controlling the membrane potential of lymphocytes (2)(3)(4)(5)(6)(7). During activation, inositol 1,4,5-triphosphate generation induces the release of Ca 2ϩ from internal stores.…”