Kv1 channel regulation by Kvβ2 dictates macrophage phenotype and immune response

All cells rely on transmembrane ion channels to set their resting membrane potential and regulate physiological processes. As the most numerous and ubiquitous class of K+ channel groups, the first family of voltage-gated potassium (Kv1) channels regulate physiological functions in various organ systems, but recently, their role in impacting immune cell activity has garnered attention. Kv1.3 is the major Kv1 isoform in immune cells, including macrophages, where it influences cytokine production and migration. Although numerous signaling pathways impact Kv channels, their interaction with specific intracellular proteins, the Kvβ subunits, are key regulators of channel stability and trafficking. Not only does Kvβ subunit presence influence the activity of Kv channels, but Kvβ has been identified as an active aldo-keto reductase (AKR) whose activity directly regulates Kv channel gating and subsequent Kv-channel mediated potassium efflux (IKv). Additionally, initial reports have demonstrated that Kvβ isoforms are differentially induced in macrophages in vitro depending on the activation stimuli. However, the functional regulation of Kv1 channels by Kvβ catalysis which may control macrophage phenotype has yet to be fully elucidated. Our preliminary data suggest that Kv1.3 is upregulated with inflammatory stimuli and that its direct pharmacological inhibition disrupts macrophage polarization and acute phagocytotic function. Further, our data indicate a role for Kvβ2 in macrophage pro-resolving functions as genetic deletion of this subunit significantly inhibited macrophage efferocytosis, in vivo. Guided by these findings, we hypothesize that macrophage activation depends on the catalytic regulation of Kv1 channels by Kvβ and that binding of specialized pro-resolving lipid mediators (SPMs) to the active site of Kvβ shifts macrophage phenotype from pro-inflammatory to pro-resolving. Using a combination of in silico prediction and in vitro binding and enzyme kinetic assays, we found that SPMs binding to Kvβ’s AKR domain may act as a central nexus that affords macrophages the ability to complete the phenotypic switch to resolution which must take place for proper cessation of inflammation. Additionally, in vivo models of acute peritonitis and efferocytosis suggest intact Kvβ2 catalysis as a necessary regulator of the fine tuning and homeostasis of these processes. Such knowledge is important because it could be used to develop more efficacious, targeted strategies to lessen chronic inflammatory challenges while mitigating the potential off-target effects of blocking the entire Kv channel pore, due to Kv channel ubiquity in most organ systems. Further, elucidation of these processes will not only enhance our understanding of mechanisms underlying fundamental macrophage biology, but the findings could also be used to develop new therapeutic avenues to diminish hyper- and chronic inflammatory pathologies. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.