Human T cells in silico: Modelling their electrophysiological behaviour in health and disease

Ehling, Petra; Meuth, Patrick; Eichinger, Paul; Herrmann, Alexander M.; Bittner, Stefan; Pawlowski, Matthias; Pankratz, Susann; Herty, Michaël; Budde, Thomas; Meuth, Sven G.

doi:10.1016/j.jtbi.2016.06.001

Cited by 9 publications

(7 citation statements)

References 78 publications

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“…These findings indicate that Kv1.3 and KCa3.1 are sufficient to regulate the T-cell response, and suggest that other K + channels such as the two-pore domain K + channel TASK1 (refs 39, 40) do not play a significant role. This validated our findings in the Kcna3 − / − rat, showing that KCa3.1 was sufficient to mediate normal activation responses in T cells normally reliant on Kv1.3 and that KCa3.1 may compensate for impaired Kv1.3 function mediated by blockers such as ShK.…”

Section: Discussionmentioning

confidence: 91%

Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions

Chiang¹,

Li²,

Jeet³

et al. 2017

Nat Commun

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Voltage-gated Kv1.3 and Ca2+-dependent KCa3.1 are the most prevalent K+ channels expressed by human and rat T cells. Despite the preferential upregulation of Kv1.3 over KCa3.1 on autoantigen-experienced effector memory T cells, whether Kv1.3 is required for their induction and function is unclear. Here we show, using Kv1.3-deficient rats, that Kv1.3 is involved in the development of chronically activated antigen-specific T cells. Several immune responses are normal in Kv1.3 knockout (KO) rats, suggesting that KCa3.1 can compensate for the absence of Kv1.3 under these specific settings. However, experiments with Kv1.3 KO rats and Kv1.3 siRNA knockdown or channel-specific inhibition of human T cells show that maximal T-cell responses against autoantigen or repeated tetanus toxoid stimulations require both Kv1.3 and KCa3.1. Finally, our data also suggest that T-cell dependency on Kv1.3 or KCa3.1 might be irreversibly modulated by antigen exposure.

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Section: Discussionmentioning

confidence: 91%

Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions

Chiang¹,

Li²,

Jeet³

et al. 2017

Nat Commun

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“…In humans, loss of function mutations of Nav1.7 lead to congenital insensitivity to pain (CIP), whereas gain of function mutations of Nav1.7 cause inherited erythermalgia (IEM) and proxysmal extreme pain disorder (PEPD) syndromes [4–6], therefore Nav1.7 antagonists should have an application in pain management. Kv1.3 regulates membrane potential and Ca 2+ signaling in T cells, and its expression is enhanced in CD4 + and CD8 + cells following T cell receptor activation [7–9]. The inhibition of Kv1.3 suppresses Ca 2+ -signaling, cytokine production, and proliferation of autoantigen-specific T cells.…”

Section: Introductionmentioning

confidence: 99%

High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE

Li¹,

Lü²,

Chiang³

et al. 2017

PLoS ONE

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Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate. In this study, we utilized SyncroPatch 768PE, one of the latest generation APC platforms which conducts parallel recording from two-384 modules with giga-seal data quality, to push these 2 boundaries. By optimizing various cell patching parameters and a two-step voltage protocol, we developed a high throughput APC assay for the voltage-gated sodium channel Nav1.7. By testing a group of Nav1.7 reference compounds’ IC50, this assay was proved to be highly consistent with manual patch clamp (R > 0.9). In a pilot screening of 10,000 compounds, the success rate, defined by > 500 MΩ seal resistance and >500 pA peak current, was 79%. The assay was robust with daily throughput ~ 6,000 data points and Z’ factor 0.72. Using the same platform, we also successfully recorded endogenous voltage-gated potassium channel Kv1.3 in primary T cells. Together, our data suggest that SyncroPatch 768PE provides a powerful platform for ion channel research and drug discovery.

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“…In addition, immune cells are also known to express members of the transient receptor potential melastatin (TRPM) channel family (TRPM2, TRPM7) [23,24], which conduct various mono-and divalent cations (sodium, calcium, potassium). This family is activated by ligand binding and its members are mainly known for their role in perceiving cold (menthol) as well as taste.…”

Section: Calcium-dependent Autoimmune Mechanismsmentioning

confidence: 99%

Calcium Homeostasis in Multiple Sclerosis

Hundehege¹,

Epping²,

Meuth³

2017

Neurology International Open

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Human T cells in silico: Modelling their electrophysiological behaviour in health and disease

Cited by 9 publications

References 78 publications

Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions

Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions

High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE

Calcium Homeostasis in Multiple Sclerosis

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