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<p>The Tandem of pore domain in a Weak Inward Rectifying K<sup>+</sup> channel 2 (TWIK-2; <i>KCNK6</i>) is a member of the Two-Pore Domain K<sup><i>+</i></sup> (K<sub>2P</sub>) channel family, which is associated with pulmonary hypertension, lung injury, and inflammation. Despite its physiological relevance, the structure, regulatory mechanisms, and selective modulators of TWIK-2 remain largely unknown. Here, we present a 3.7 Å single particle cryo-electron microscopy structure of human TWIK-2 and highlight its conserved and distinctive features. Using automated whole-cell patch clamp recordings, we demonstrate that gating in TWIK-2 is voltage-dependent and insensitive to changes in the extracellular pH. We identify key residues that influence TWIK-2 activity by employing site-directed mutagenesis and provide insights into the possible lipid-mediated mechanism of TWIK-2 regulation. Additionally, we demonstrate the application of high-throughput automated whole-cell patch clamp platforms to screen small molecule modulators of TWIK-2. Our work serves as a foundation for designing high-throughput small molecule screening campaigns to identify specific high-affinity TWIK-2 modulators, including promising- anti-inflammatory therapeutics.</p>

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Insights into the structure and modulation of human TWIK-2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月31日

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  • Qianqian Ma,
  • Ciria C. Hernandez,
  • Vikas Navratna,
  • Arvind Kumar,
  • Jaimin K. Rana,
  • Jiameng Zong,
  • Abraham Lee,
  • Shyamal Mosalaganti

摘要

The Tandem of pore domain in a Weak Inward Rectifying K+ channel 2 (TWIK-2; KCNK6) is a member of the Two-Pore Domain K+ (K2P) channel family, which is associated with pulmonary hypertension, lung injury, and inflammation. Despite its physiological relevance, the structure, regulatory mechanisms, and selective modulators of TWIK-2 remain largely unknown. Here, we present a 3.7 Å single particle cryo-electron microscopy structure of human TWIK-2 and highlight its conserved and distinctive features. Using automated whole-cell patch clamp recordings, we demonstrate that gating in TWIK-2 is voltage-dependent and insensitive to changes in the extracellular pH. We identify key residues that influence TWIK-2 activity by employing site-directed mutagenesis and provide insights into the possible lipid-mediated mechanism of TWIK-2 regulation. Additionally, we demonstrate the application of high-throughput automated whole-cell patch clamp platforms to screen small molecule modulators of TWIK-2. Our work serves as a foundation for designing high-throughput small molecule screening campaigns to identify specific high-affinity TWIK-2 modulators, including promising- anti-inflammatory therapeutics.