Exploring the Regulation of Kv1.2 Homomeric and Heteromeric Channels by Redox, LMAN2, and Kvβ

• Author / Creator

  Wong, Anson

• Voltage-gated potassium channels generate diverse current properties influenced by various signaling mechanisms that are still not well understood. Among these channels, Kv1.2 in particular demonstrates highly variable activation properties based on their ability to shift between a fast permissive and slow resistant gating mode. This feature is coined “slow gating regulation” and is sensitive to modulation by extrinsic factors. Reducing agents can promote the resistant gating mode resulting in a profound depolarizing shift of voltage-dependence and use-dependent activation. Similarly, overexpression of Kv1.2 channels with transmembrane lectin LMAN2 recapitulates these functional outcomes. It remains uncertain whether Kv1.2 redox and LMAN2 sensitivity is present in Kv1 heteromeric channels and also whether these mechanisms are interconnected.
  In my thesis, I report that redox and LMAN2 sensitivity are exclusive to Kv1.2 among Kv1 homomeric channels and can persist in Kv1.2-containing heteromeric channels. These findings demonstrate that Kv1.2 can act as an adaptor subunit capable of recruiting sensitivity to redox and LMAN2 to other Kv1 channels. Additionally, it highlights the overlapping subunit dependence (i.e. Kv1.2 α-subunits) of redox and LMAN2, supporting LMAN2 as a redox-sensitive auxiliary subunit that regulates Kv1.2 slow gating. Furthermore, my research reveals that multiple signaling pathways can simultaneously regulate ion channels, leading to even greater current diversity. Redox and LMAN2- mediated slow gating strongly suppress Kvβ and Kv1.4-mediated inactivation by decelerating channel opening. This inhibitory effect can then be rescued through depolarizing prepulses or mutagenesis targeting redox/LMAN2 sensitivity.
  Overall, this thesis expands our understanding of Kv1.2 channel modulation, highlights the profound impact of extrinsic regulatory mechanisms, and provides a solid foundation for future investigations into ion channel regulation.

• Subjects / Keywords

  • potassium channels
  • Kv
  • LMAN2
  • electrophysiology

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-q2dr-6p58

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.