HIF-1α–mediated upregulation of TASK-2 K+ channels augments Ca2+ signaling in mouse B cells under hypoxia

DH Shin, H Lin, H Zheng, KS Kim, JY Kim… - The Journal of …, 2014 - journals.aai.org
DH Shin, H Lin, H Zheng, KS Kim, JY Kim, YS Chun, JW Park, JH Nam, WK Kim, YH Zhang…
The Journal of Immunology, 2014journals.aai.org
The general consensus is that immune cells are exposed to physiological hypoxia in vivo
(PhyO 2, 2–5% P O2). However, functional studies of B cells in hypoxic conditions are
sparse. Recently, we reported the expression in mouse B cells of TASK-2, a member of pH-
sensitive two-pore domain K+ channels with background activity. In this study, we
investigated the response of K+ channels to sustained PhyO 2 (sustained hypoxia [SH], 3%
P O2 for 24 h) in WEHI-231 mouse B cells. SH induced voltage-independent background K+ …
Abstract
The general consensus is that immune cells are exposed to physiological hypoxia in vivo (PhyO 2, 2–5% P O2). However, functional studies of B cells in hypoxic conditions are sparse. Recently, we reported the expression in mouse B cells of TASK-2, a member of pH-sensitive two-pore domain K+ channels with background activity. In this study, we investigated the response of K+ channels to sustained PhyO 2 (sustained hypoxia [SH], 3% P O2 for 24 h) in WEHI-231 mouse B cells. SH induced voltage-independent background K+ conductance (SH-K bg) and hyperpolarized the membrane potential. The pH sensitivity and the single-channel conductance of SH-K bg were consistent with those of TASK-2. Immunoblotting assay results showed that SH significantly increased plasma membrane expressions of TASK-2. Conversely, SH failed to induce any current following small interfering (si) TASK-2 transfection. Similar hypoxic upregulation of TASK-2 was also observed in splenic primary B cells. Mechanistically, upregulation of TASK-2 by SH was prevented by si hypoxia-inducible factor-1α (HIF-1α) transfection or by YC-1, a pharmacological HIF-1α inhibitor. In addition, TASK-2 current was increased in WEHI-231 cells overexpressed with O 2-resistant HIF-1α. Importantly,[Ca 2+] c increment in response to BCR stimulation was significantly higher in SH-exposed B cells, which was abolished by high K+-induced depolarization or by siTASK-2 transfection. The data demonstrate that TASK-2 is upregulated under hypoxia via HIF-1α–dependent manner in B cells. This is functionally important in maintaining the negative membrane potential and providing electrical driving force to control Ca 2+ influx.
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