Pattern of Kvβ Subunit Expression in Macrophages Depends upon Proliferation and the Mode of Activation

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Abstract
Voltage-dependent potassium channels (Kv) in leukocytes are involved in the immune response. In bone marrow-derived macrophages (BMDM), proliferation and activation induce delayed rectifier K+ currents, generated by Kv1.3, via transcriptional, translational, and posttranslational controls. Furthermore, modulatory Kvβ subunits coassociate with Kvα subunits, increasing channel diversity and function. In this study we have identified Kvβ subunits in mouse BMDM, studied their regulation during proliferation and activation, and analyzed K+ current parameters influenced by these proteins. BMDM express all isoforms of Kvβ1 (Kvβ1.1, Kvβ1.2, and Kvβ1.3) and Kvβ2 (Kvβ2.1), but not Kvβ4, the alternatively spliced murine Kvβ3 variant. M-CSF-dependent proliferation induced all Kvβ isoforms. However, LPS- and TNF-α-induced activation differentially regulated these subunits. Although LPS increased Kvβ1.3, reduced Kvβ1.2, and maintained Kvβ1.1 mRNA levels constant, TNF-α up-regulated Kvβ1.1, down-regulated Kvβ1.2, and left Kvβ1.3 expression unchanged. Moreover, in contrast to TNF-α, M-CSF- and LPS- up-regulated Kvβ2.1. K+ currents from M-CSF- and LPS-stimulated BMDM exhibited faster inactivation, whereas TNF-α increased τ values. Although in M-CSF-stimulated cells the half-inactivation voltage shifted to more positive potentials, the incubation with LPS and TNF-α resulted in a hyperpolarizing displacement similar to that in resting BMDM. Furthermore, activation time constants of K+ currents and the kinetics of the tail currents were different depending upon the mode of activation. Our results indicate that differential Kvβ expression modifies the electrical properties of Kv in BMDM, dependent upon proliferation and the mode of activation. This could determine physiologically appropriate surface channel complexes, allowing for greater flexibility in the precise regulation of the immune response.