Extracellular K 1 and Opening of Voltage-gated Potassium Channels Activate T Cell Integrin Function: Physical and Functional Association between Kv1.3 Channels and b 1 Integrins

Elevated extracellular K 1 ([K 1 ] o ), in the absence of “classical” immunological stimulatory signals, was found to itself be a sufficient stimulus to activate T cell b 1 integrin moieties, and to induce integrin-mediated adhesion and migration. Gating of T cell voltage-gated K 1 channels (Kv1.3) appears to be the crucial “decision-making” step, through which various physiological factors, including elevated [K 1 ] o levels, affect the T cell b 1 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 1 b , the neuropeptide calcitonin gene–related peptide (CGRP), as well as elevated [K 1 ] 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 b 1 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 1 ] 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.