Antibody-guided photoablation of voltage-gated potassium currents.
Antibody-guided photoablation of voltage-gated potassium currents.
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DOI：
10.1085/jgp.201311023
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Trimmer JS
中科院分区：
文献类型：
--
作者：
Sack JT;Stephanopoulos N;Austin DC;Francis MB;Trimmer JS
一个由40个哺乳动物电压门控钾（Kv）通道组成的家族控制电兴奋细胞的膜兴奋性。单个Kv通道类型对电生理信号传导的贡献一直难以分配，因为对于单个Kv亚基存在很少的选择性抑制剂。在免疫系统相互作用的精致选择性的指导下，我们发现抗体缀合物作为选择性Kv抑制剂的潜力。在这里，功能良性的抗Kv通道单克隆抗体（mAb）进行化学修饰，以促进光消融的K电流。将抗体与卟啉化合物缀合，所述卟啉化合物在光刺激时造成局部氧化损伤。抗Kv4.2单克隆抗体-卟啉缀合物促进Kv4.2电流的光消融。K电流的消融程度与光子剂量和共轭物浓度有关。Kv通道光消融对Kv4.2的选择性超过Kv4.3或Kv2.1，产生现有神经毒素或其他Kv通道抑制剂中不存在的特异性。我们得出结论，抗体卟啉共轭物能够选择性光消融的KV电流。这些发现表明，本身不调节离子通道功能的亚型特异性mAb能够将功能性有效载荷递送至特异性离子通道靶标。
A family of 40 mammalian voltage-gated potassium (Kv) channels control membrane excitability in electrically excitable cells. The contribution of individual Kv channel types to electrophysiological signaling has been difficult to assign, as few selective inhibitors exist for individual Kv subunits. Guided by the exquisite selectivity of immune system interactions, we find potential for antibody conjugates as selective Kv inhibitors. Here, functionally benign anti-Kv channel monoclonal antibodies (mAbs) were chemically modified to facilitate photoablation of K currents. Antibodies were conjugated to porphyrin compounds that upon photostimulation inflict localized oxidative damage. Anti-Kv4.2 mAb–porphyrin conjugates facilitated photoablation of Kv4.2 currents. The degree of K current ablation was dependent on photon dose and conjugate concentration. Kv channel photoablation was selective for Kv4.2 over Kv4.3 or Kv2.1, yielding specificity not present in existing neurotoxins or other Kv channel inhibitors. We conclude that antibody–porphyrin conjugates are capable of selective photoablation of Kv currents. These findings demonstrate that subtype-specific mAbs that in themselves do not modulate ion channel function are capable of delivering functional payloads to specific ion channel targets.
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DOI：
10.1084/jem.177.3.637
发表时间：
1993-03-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lin CS;Boltz RC;Blake JT;Nguyen M;Talento A;Fischer PA;Springer MS;Sigal NH;Slaughter RS;Garcia ML
通讯作者：
Garcia ML
DOI：
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发表时间：
2011-07
期刊：
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影响因子：
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作者：
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Golab J
影响因子：
4.3
作者：
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通讯作者：
Majima, Tetsuro
DOI：
10.1085/jgp.201110712
发表时间：
2012-01
期刊：
The Journal of general physiology
影响因子：
--
作者：
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通讯作者：
Verkman AS
影响因子：
64.8
作者：
DECOURSEY, TE;CHANDY, KG;CAHALAN, MD
通讯作者：
CAHALAN, MD