Extracellular K(+) and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and beta1 integrins.
Elevated extracellular K(+) ([K(+)](o)), in the absence of "classical" immunological stimulatory signals, was found to itself be a sufficient stimulus to activate T cell beta1 integrin moieties, and to induce integrin-mediated adhesion and migration. Gating of T cell voltage-gated K(+) channels (Kv1.3) appears to be the crucial "decision-making" step, through which various physiological factors, including elevated [K(+)](o) levels, affect the T cell beta1 integrin function: opening of the channel leads to function, whereas its blockage prevents it. In support of this notion, we found that the proadhesive effects of the chemokine macrophage-inflammatory protein 1beta, the neuropeptide calcitonin gene-related peptide (CGRP), as well as elevated [K(+)](o) levels, are blocked by specific Kv1.3 channel blockers, and that the unique physiological ability of substance P to inhibit T cell adhesion correlates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the beta1 integrins coimmunoprecipitate, suggesting that their physical association underlies their functional cooperation on the T cell surface. This study shows that T cells can be activated and driven to integrin function by a pathway that does not involve any of its specific receptors (i.e., by elevated [K(+)](o)). In addition, our results suggest that undesired T cell integrin function in a series of pathological conditions can be arrested by molecules that block the Kv1.3 channels.
Levite
M
M
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. mia.levite@weizmann.ac.il
Cahalon
L
L
Peretz
A
A
Hershkoviz
R
R
Sobko
A
A
Ariel
A
A
Desai
R
R
Attali
B
B
Lider
O
O
D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity; D054407:Chemokine CCL4; D004553:Electric Conductivity; D006801:Humans; D019012:Integrin beta1 / Q000276:immunology*; D015640:Ion Channel Gating / Q000502:physiology*; D051664:Kv1.3 Potassium Channel; D008213:Lymphocyte Activation / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D011188:Potassium / Q000276:immunology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000276:immunology*; D024642:Potassium Channels, Voltage-Gated; D013373:Substance P / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology
D054407:Chemokine CCL4; D019012:Integrin beta1; C496973:KCNA3 protein, human; D051664:Kv1.3 Potassium Channel; D019402:Macrophage Inflammatory Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013373:Substance P; D011188:Potassium