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Jianmin Cui

Jianmin Cui

Washington University in St. Louis, USA

Title: PIP2 modulation of KCNQ1 channels

Biography

Biography: Jianmin Cui

Abstract

Voltage-gated ion channels generate dynamic ionic currents that are vital to the physiological functions of many tissues. These proteins contain separate voltage-sensing domains, which detect changes in transmembrane voltage, and pore domains, which conduct ions. Coupling of voltage sensing and pore opening is critical to the channel function and has been modeled as a protein–protein interaction between the two domains. However, our data show that coupling in Kv7.1 channels requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP2). We found that voltage-sensing domain activation failed to open the pore in the absence of PIP2. This result is due to loss of coupling because PIP2 was also required for pore opening to affect voltage-sensing domain activation. We identified a critical site for PIP2-dependent coupling at the interface between the voltage-sensing domain and the pore domain. This site is actually a conserved lipid-binding site among different K+ channels, suggesting that lipids play an important role in coupling in many ion channels. To further investigate the mechanism of PIP2 mediated VSD-pore coupling, we identified a compound that mimics PIP2 structure and function as a molecular probe. This compound was identified using an in silico screening approach based on molecular docking of a library of compounds to the PIP2 binding site in a homology model of the Kv7.1 channel. Our results show that this compound can substitute PIP2 in activating the Kv7.1 channel.

References:

  1. Cui, J. (2016) Voltage dependent gating: novel insights from KCNQ1 channels. Biophys J 110:14-25.  
  2. Kasimova M, Zaydman M, Cui J, Tarek M (2015) PIP2-dependent coupling is prominent in Kv7.1 due to weakened S4-S5/S6 interactions. Scientific Reports 5:7474.
  3. Zaydman, M.A. and Cui, J. (2014) PIP2 activation of KCNQ channels. Front Physiol. 5:195. doi: 10.3389/fphys.2014.00195.
  4. Zaydman M, Kasimova M, McFarland K, Liang H, Beller Z, Shi J, Hou P, Kinser H, Zhang G, Tarek M, and Cui J (2014) Domain-domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel. eLife 2014;3:e03606.
  5. Zaydman MA, Silva JR, Delaloye K, Li Y, Liang H, Larsson HP, Shi J, and Cui J (2013) Kv7.1 ion channels require PIP2 to couple voltage sensing to pore opening. Proc. Natl. Acad. Sci., U.S.A.  110:13180-13185.