Extracellular K+ and opening of voltage-gated potassium channels activate T cell integrin function:: Physical and functional association between Kv1.3 channels and β1 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 beta 1 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 beta 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 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 correlates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the pi integrins coimmunoprecipitate, suggesting that their physical association underlies their functional cooperation on the T cell surface. This study shows that T cells call be activated and driven to integrin function by a pathway 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 molecules that block the Kv1.3 channels.