Lee Jun-Ho, Park Chul-Kyu, Chen Gang, Han Qingjian, Xie Rou-Gang, Liu Tong, Ji Ru-Rong, Lee Seok-Yong
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Cell. 2014 Jun 5;157(6):1393-1404. doi: 10.1016/j.cell.2014.03.064. Epub 2014 May 22.
Voltage-gated sodium (NaV) channels control the upstroke of the action potentials in excitable cells. Multiple studies have shown distinct roles of NaV channel subtypes in human physiology and diseases, but subtype-specific therapeutics are lacking and the current efforts have been limited to small molecules. Here, we present a monoclonal antibody that targets the voltage-sensor paddle of NaV1.7, the subtype critical for pain sensation. This antibody not only inhibits NaV1.7 with high selectivity, but also effectively suppresses inflammatory and neuropathic pain in mice. Interestingly, the antibody inhibits acute and chronic itch despite well-documented differences in pain and itch modulation. Using this antibody, we discovered that NaV1.7 plays a key role in spinal cord nociceptive and pruriceptive synaptic transmission. Our studies reveal that NaV1.7 is a target for itch management, and the antibody has therapeutic potential for suppressing pain and itch. Our antibody strategy may have broad applications for voltage-gated cation channels.
电压门控钠（NaV）通道控制可兴奋细胞动作电位的上升支。多项研究表明NaV通道亚型在人体生理和疾病中具有不同作用，但缺乏亚型特异性疗法，目前的努力仅限于小分子。在此，我们展示了一种靶向NaV1.7电压传感器桨叶的单克隆抗体，NaV1.7是对痛觉至关重要的亚型。该抗体不仅以高选择性抑制NaV1.7，还能有效抑制小鼠的炎性和神经性疼痛。有趣的是，尽管疼痛和瘙痒调节存在诸多差异，但该抗体仍能抑制急性和慢性瘙痒。利用这种抗体，我们发现NaV1.7在脊髓伤害性和瘙痒性突触传递中起关键作用。我们的研究表明NaV1.7是瘙痒治疗的靶点，该抗体具有抑制疼痛和瘙痒的治疗潜力。我们的抗体策略可能在电压门控阳离子通道方面有广泛应用。
