The influence of protons and zinc ions on the steady-state inactivation of Kv1.3 potassium channels

Teisseyre, Andrzej; Mozrzymas, Jerzy W.

doi:10.2478/s11658-006-0067-6

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…The delayed rectifier current I Kv1.3 was realized by adapting the membrane mechanism I KD from a Purkinje cell model (31). Shifting the half-maximum activation and inactivation to Ϫ28.8 and Ϫ57.8 mV, respectively, led to a current that matches the slowly inactivating current component seen in human T cells (32,33). The maximum specific conductance gkbar was set to 0.0023 S/cm 2 to reach a maximum current of about 200 pA at a membrane potential of ϩ40 mV.…”

Section: Methodsmentioning

confidence: 99%

TWIK-related Acid-sensitive K+ Channel 1 (TASK1) and TASK3 Critically Influence T Lymphocyte Effector Functions

Meuth

Bittner

Meuth³

et al. 2008

Journal of Biological Chemistry

100

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Two major K؉ channels are expressed in T cells, (i) the voltagedependent K V 1.3 channel and (ii) the Ca 2؉ -activated K ؉ channel KCa 3.1 (IKCa channel). Both critically influence T cell effector functions in vitro and animal models in vivo. Here we identify and characterize TWIK-related acid-sensitive potassium channel 1 (TASK1) and TASK3 as an important third K ؉ conductance on T lymphocytes. T lymphocytes constitutively express TASK1 and -3 protein. Application of semi-selective TASK blockers resulted in a significant reduction of cytokine production and cell proliferation. Interference with TASK channels on CD3؉ T cells revealed a dose-dependent reduction (ϳ40%) of an outward current in patch clamp recordings indicative of TASK channels, a finding confirmed by computational modeling. In vivo relevance of our findings was addressed in an experimental model of multiple sclerosis, adoptive transfer experimental autoimmune encephalomyelitis. Pre-treatment of myelin basic protein-specific encephalitogenic T lymphocytes with TASK modulators was associated with significant amelioration of the disease course in Lewis rats. These data introduce K 2 P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders.The last decade has revealed much knowledge about the intracellular events accompanied by T lymphocyte activation following recognition of antigens bound to major histocompatibility complexes. K ϩ selective ion channels in T cells and their role in immune responses have been discussed for decades, since the discovery that non-selective K ϩ blockers could inhibit T cell proliferation in vitro (1-3). The role of K ϩ channels in the activation of T cells is pivotal, because opening the channels hyperpolarizes the membrane potential, which in turn increases the influx of Ca 2ϩ via Ca 2ϩ release-activated Ca Intracellular Ca 2ϩ release triggers activation of CRAC channels resulting in longer lasting (ϳ1 h) elevated [Ca 2ϩ ] i mandatory for further transcription-dependent steps of T cell activation (4, 6). With the combined use of patch clamp electrophysiology and molecular biology, the voltage-dependent K ϩ channel 1.3 (K V 1.3 channel) and the intermediate conductance Ca 2ϩ -activated channel (IKCa channel; IK Ca 1 or K Ca 3.1; which acquires its Ca 2ϩ dependence from constitutively bound calmodulin) were found to be the dominating K ϩ channel types expressed in T cells (7-10). K V 1.3 is activated by membrane depolarization, whereas K Ca 3.1 channel opening is triggered by a rise in Ca 2ϩ ions (5). Selective blockade of K V 1.3 leads to suppression of T cell effector function, e.g. decreased cytokine release and suppression of proliferation (11,12). Underlining this finding, in vivo blockade of K V 1.3 has been shown to mediate beneficial effects in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis (12,13). The importance of K ϩ ch...

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Section: Methodsmentioning

confidence: 99%

TWIK-related Acid-sensitive K+ Channel 1 (TASK1) and TASK3 Critically Influence T Lymphocyte Effector Functions

Meuth

Bittner

Meuth³

et al. 2008

Journal of Biological Chemistry

100

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“…One is related to the screening of the surface charges when the H + concentration is increased, i.e., pH e is lowered. Screening of the surface charges will affect the operation of the voltage sensor domain (VSD) of voltage-gated channels, as was demonstrated for Shaker ( Broomand et al, 2007 ) and Kv1.3 ( Deutsch and Lee, 1989 ; Teisseyre and Mozrzymas, 2007 ), among others. KCa3.1 lacks the charged S4 helix in the VSD and is not a voltage-gated ion channel, therefore, the lack of the effect of pH e on the K + conductance in KCa3.1 is not surprising.…”

Section: Discussionmentioning

confidence: 99%

Intracellular acidity impedes KCa3.1 activation by Riluzole and SKA-31

Cozzolino,

Panyi

2024

Front. Pharmacol.

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Background:The unique microenvironment in tumors inhibits the normal functioning of tumor-infiltrating lymphocytes, leading to immune evasion and cancer progression. Over-activation of KCa3.1 using positive modulators has been proposed to rescue the anti-tumor response. One of the key characteristics of the tumor microenvironment is extracellular acidity. Herein, we analyzed how intra- and extracellular pH affects K+ currents through KCa3.1 and if the potency of two of its positive modulators, Riluzole and SKA-31, is pH sensitive.Methods:Whole-cell patch-clamp was used to measure KCa3.1 currents either in activated human peripheral lymphocytes or in CHO cells transiently transfected with either the H192A mutant or wild-type hKCa3.1 in combination with T79D-Calmodulin, or with KCa2.2.Results:We found that changes in the intra- and extracellular pH minimally influenced the KCa3.1-mediated K+ current. Extracellular pH, in the range of 6.0–8.0, does not interfere with the capacity of Riluzole and SKA-31 to robustly activate the K+ currents through KCa3.1. Contrariwise, an acidic intracellular solution causes a slow, but irreversible loss of potency of both the activators. Using different protocols of perfusion and depolarization we demonstrated that the loss of potency is strictly time and pH-dependent and that this peculiar effect can be observed with a structurally similar channel KCa2.2. While two different point mutations of both KCa3.1 (H192A) and its associated protein Calmodulin (T79D) do not limit the effect of acidity, increasing the cytosolic Ca2+ concentration to saturating levels eliminated the loss-of-potency phenotype.Conclusion:Based on our data we conclude that KCa3.1 currents are not sensitive the either the intracellular or the extracellular pH in the physiological and pathophysiological range. However, intracellular acidosis in T cells residing in the tumor microenvironment could hinder the potentiating effect of KCa3.1 positive modulators administered to boost their activity. Further research is warranted both to clarify the molecular interactions between the modulators and KCa3.1 at different intracellular pH conditions and to define whether this loss of potency can be observed in cancer models as well.

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“…On the other hand, the high concentration of protons in TME may also strongly affect the biological functions of these pH-sensitive proteins and receptors, since it may induce Kv1.3 potassium channel inactivation, and the alteration of the signalling pathway mediated by the Ca 2+ -permeable channels, TRPM8 and Piezo1 [91][92][93], ultimately altering their proaptoptotic signalling. However, the acid-mediated effect on these ion channels and the downstream signalling has never been explored in sarcoma.…”

Section: Ph Sensors In Sarcoma Cellsmentioning

confidence: 99%

Acid Microenvironment in Bone Sarcomas

Pompo

Cortini

Baldini

et al. 2021

Cancers

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In bone sarcomas, extracellular proton accumulation is an intrinsic driver of malignancy. Extracellular acidosis increases stemness, invasion, angiogenesis, metastasis, and resistance to therapy of cancer cells. It reprograms tumour-associated stroma into a protumour phenotype through the release of inflammatory cytokines. It affects bone homeostasis, as extracellular proton accumulation is perceived by acid-sensing ion channels located at the cell membrane of normal bone cells. In bone, acidosis results from the altered glycolytic metabolism of bone cancer cells and the resorption activity of tumour-induced osteoclasts that share the same ecosystem. Proton extrusion activity is mediated by extruders and transporters located at the cell membrane of normal and transformed cells, including vacuolar ATPase and carbonic anhydrase IX, or by the release of highly acidic lysosomes by exocytosis. To date, a number of investigations have focused on the effects of acidosis and its inhibition in bone sarcomas, including studies evaluating the use of photodynamic therapy. In this review, we will discuss the current status of all findings on extracellular acidosis in bone sarcomas, with a specific focus on the characteristics of the bone microenvironment and the acid-targeting therapeutic approaches that are currently being evaluated.

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The influence of protons and zinc ions on the steady-state inactivation of Kv1.3 potassium channels

Cited by 5 publications

References 21 publications

TWIK-related Acid-sensitive K+ Channel 1 (TASK1) and TASK3 Critically Influence T Lymphocyte Effector Functions

TWIK-related Acid-sensitive K+ Channel 1 (TASK1) and TASK3 Critically Influence T Lymphocyte Effector Functions

Intracellular acidity impedes KCa3.1 activation by Riluzole and SKA-31

Acid Microenvironment in Bone Sarcomas

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