TY - JOUR TI - Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1 AU - Srivastava, Shekhar AU - Panda, Saswati AU - Li, Zhai AU - Fuhs, Stephen R AU - Hunter, Tony AU - Thiele, Dennis J AU - Hubbard, Stevan R AU - Skolnik, Edward Y A2 - Davis, Roger J VL - 5 PY - 2016 DA - 2016/08/19 SP - e16093 C1 - eLife 2016;5:e16093 DO - 10.7554/eLife.16093 UR - https://doi.org/10.7554/eLife.16093 AB - KCa2.1, KCa2.2, KCa2.3 and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NDPK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes. Here, we demonstrate that phosphorylation of His358 activates KCa3.1 by antagonizing copper-mediated inhibition of the channel. Furthermore, we show that activated CD4+ T cells deficient in intracellular copper exhibit increased KCa3.1 histidine phosphorylation and channel activity, leading to increased calcium flux and cytokine production. These findings reveal a novel regulatory mechanism for a mammalian potassium channel and for T-cell activation, and highlight a unique feature of histidine versus serine/threonine and tyrosine as a regulatory phosphorylation site. KW - potassium channel KW - histidine phosphorylation KW - copper inhibition JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -