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演題詳細

Oral

イオンチャンネル、興奮性膜
Ion Channels and Excitable Membranes

開催日 2014/9/11
時間 14:00 - 15:00
会場 Room J(313+314)
Chairperson(s) 橋本 浩一 / Kouichi Hashimoto (広島大学医歯薬保健学研究院 神経生理学 / Department of Neurophysiology, Hiroshima University, Japan)
福井 巌 / Iwao Fukui (京都大学大学院 医学研究科 神経生物学 / Physiology & Neurobiology, Faculty of Medicine, Kyoto University, Japan)


PIP2 regulation on the pharmacological selectivity and gating of KCNQ channels

  • O1-J-3-2
  • Pingzheng Zhou:1 Haibo Yu:2 Min Gu:1 Fajun Nan:1 Zhaobing Gao:1 Min Li:2 
  • 1:State Key Laboratory of Drug Research and Chinese National Drug Screening Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China 2:The Solomon H. Snyder Department of Neuroscience and High Throughput Biology Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 

Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as
retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by
dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1 - KCNQ5) are
found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents.
We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and
zinc pyrithione (ZnPy). Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2)
causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of
pharmacological selectivity caused by PIP2 may be induced orthogonally by voltage-sensitive
phosphatase, or conversely, abolished by mutating a PIP2 site within the S4-S5 linker of KCNQ3.
Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is
dynamic and may be regulated by receptor signaling pathways via PIP2.
We also show that PIP2 preferentially interacts with the S4-S5 linker in the open-state KCNQ2
channel, whereas it contacts the S2-S3 loop in the closed state. These interactions are different
from the PIP2-Shaker and PIP2-Kv1.2 interactions. Disruption of the interaction of PIP2 with the
S4-S5 linker by a single mutation decreases the voltage sensitivity and current amplitude, whereas
disruption of the interaction with the S2 -S3 loop does not alter voltage sensitivity. These results
provide insight into the mechanism of PIP2 action on KCNQ channels.

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