Original Article

Extracellular K⁺ and Opening of Voltage-gated Potassium Channels Activate T Cell Integrin Function: Physical and Functional Association between Kv1.3 Channels and ß1 Integrins

Correspondence to: Mia Levite, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. Tel:972-8-9343556 Fax:972-8-9344173 E-mail:mia.levite{at}weizmann.ac.il.

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 ß1 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 ß1 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 1ß, 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 ß1 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.

Key Words: T cells, extracellular K⁺, potassium channels, integrins, neuroimmunomodulation

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