Extracellular K+ and opening of voltage-gated potassium channels activate T cell integrin function: Physical and functional association between Kv1.3channels and beta 1 integrins

Elevated extracellular K+ ([K+](o)), in the absence of "classical" immunolo gical stimulatory signals, was found to itself be a sufficient stimulus to activate T cell beta 1 integrin moieties, and to induce integrin-mediated a dhesion and migration. Gating of T cell voltage-gated K+ channels (Kv1.3) a ppears to be the crucial "decision-making" step, through which various phys iological factors, including elevated [K+](o) levels, affect the T cell bet a 1 integrin function: opening of the channel leads to function, whereas it s blockage prevents it. In support of this notion, we found that the proadh esive effects of the chemokine macrophage-inflammatory protein 1 beta, 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 corr elates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the pi integrins coimmunoprecipitate, suggesting that their physical association u nderlies their functional cooperation on the T cell surface. This study sho ws that T cells call be activated and driven to integrin function by a path way that does not involve ally 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 molecule s that block the Kv1.3 channels.