Molecular Physiology Laboratory, Departament de Bioquímica i Biología Molecular, Institut de Biomedicina, Universitat de Barcelona, E-08028 Barcelona, Spain.
J Gen Physiol. 2010 Feb;135(2):135-47. doi: 10.1085/jgp.200910334.
Voltage-dependent potassium (K(v)) channels play a pivotal role in the modulation of macrophage physiology. Macrophages are professional antigen-presenting cells and produce inflammatory and immunoactive substances that modulate the immune response. Blockage of K(v) channels by specific antagonists decreases macrophage cytokine production and inhibits proliferation. Numerous pharmacological agents exert their effects on specific target cells by modifying the activity of their plasma membrane ion channels. Investigation of the mechanisms involved in the regulation of potassium ion conduction is, therefore, essential to the understanding of potassium channel functions in the immune response to infection and inflammation. Here, we demonstrate that the biophysical properties of voltage-dependent K(+) currents are modified upon activation or immunosuppression in macrophages. This regulation is in accordance with changes in the molecular characteristics of the heterotetrameric K(v)1.3/K(v)1.5 channels, which generate the main K(v) in macrophages. An increase in K(+) current amplitude in lipopolysaccharide-activated macrophages is characterized by a faster C-type inactivation, a greater percentage of cumulative inactivation, and a more effective margatoxin (MgTx) inhibition than control cells. These biophysical parameters are related to an increase in K(v)1.3 subunits in the K(v)1.3/K(v)1.5 hybrid channel. In contrast, dexamethasone decreased the C-type inactivation, the cumulative inactivation, and the sensitivity to MgTx concomitantly with a decrease in K(v)1.3 expression. Neither of these treatments apparently altered the expression of K(v)1.5. Our results demonstrate that the immunomodulation of macrophages triggers molecular and biophysical consequences in K(v)1.3/K(v)1.5 hybrid channels by altering the subunit stoichiometry.
电压门控钾 (K(v)) 通道在调节巨噬细胞生理功能方面发挥着关键作用。巨噬细胞是专业的抗原呈递细胞，可产生调节免疫反应的炎症和免疫活性物质。特定拮抗剂阻断 K(v) 通道可减少巨噬细胞细胞因子的产生并抑制增殖。许多药理学药物通过改变其质膜离子通道的活性来对特定靶细胞发挥作用。因此，研究钾离子传导调节的机制对于理解钾通道在感染和炎症免疫反应中的功能至关重要。在这里，我们证明了巨噬细胞激活或免疫抑制时，电压门控 K(+)电流的生物物理特性会发生改变。这种调节与异四聚体 K(v)1.3/K(v)1.5 通道的分子特征变化一致，该通道在巨噬细胞中产生主要的 K(v)。脂多糖激活的巨噬细胞中 K(+)电流幅度的增加表现为更快的 C 型失活、更大比例的累积失活以及对马加毒素 (MgTx) 的抑制作用比对照细胞更强。这些生物物理参数与 K(v)1.3 亚基在 K(v)1.3/K(v)1.5 杂合通道中的增加有关。相比之下，地塞米松降低了 C 型失活、累积失活和对 MgTx 的敏感性，同时降低了 K(v)1.3 的表达。这些处理都没有明显改变 K(v)1.5 的表达。我们的结果表明，巨噬细胞的免疫调节通过改变亚基比例，触发 K(v)1.3/K(v)1.5 杂合通道的分子和生物物理后果。
