Arachidonic acid is a substrate for a variety of pro-inflammatory mediators, which are generated by cyclo-oxygenases, lipoxygenases (LOX), and cytochrome P450 (CYP450) enzymes. Cyclo-oxygenase (e.g. prostaglandins and prostacyclins) and lipoxygenase (e.g. leukotrienes) products have well established pro-inflammatory roles (4), however, little is known about the functions of CYP450 products in leukocytes. We previously found that mechanical strain, generated by subjecting lymphocytes to hypotonic challenge, triggers arachidonic acid (AA) production and that two CYP450 products of AA, 5,6-epoxyeicosatrienoic acid (5,6-EET) and 20-hydroxyeicosatetraenoic (20-HETE), and a product of LOX 5-(S)-hydroperoxy-eicosatetraenoic acid (5-HPETE) induce Ca²⁺ entry in primary B cells. The main goal of these studies, therefore, was to define the biophysically properties of eicosanoid-activated channels responsible for Ca²⁺ entry and the physiologic consequences of activating these channels, including their role in mechanical signaling. We found that 5,6-EET, 20-HETE, and 5-HPETE each activate distinct calcium-permeant non-selective cation channels (NSCCs) in primary B cells. These NSCCs each regulate the plasma membrane potential and B cell adhesion to integrin ligands ICAM-1 and VCAM-1. Thus, our data demonstrate that pro-inflammatory mediators produced in response to osmotic/physical stress play a direct role in regulating the B cell membrane potential and their adhesion to specific extracellular matrix proteins. These results have important implications for understanding normal mechanisms of B cell activation, differentiation, and trafficking, but also point to novel targets for modulating the pathogenesis of B cell mediated inflammatory diseases.