期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 50, 页码 20093-20098出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1312483110
关键词
lipid; membrane; membrane protein; M current
资金
- State Key Program of Basic Research of China [2013CB910604, 2009CB918502]
- National Natural Science Foundation of China [81173027, 81072579, 81230076, 21210003]
- National Institutes of Health [U54 MH084691]
- Shanghai Science and Technology Development Funds [12QA1404000, 13JC1406700]
- Special Research Foundation of Chinese Academy of Sciences [61327014]
- Hi-Tech Research and Development Program of China [2012AA020302, 2012AA01A305]
- SA-SIBS Scholarship Program
The S4 segment and the S4-S5 linker of voltage-gated potassium (Kv) channels are crucial for voltage sensing. Previous studies on the Shaker and Kv1.2 channels have shown that phosphatidylinositol-4,5-bisphosphate (PIP2) exerts opposing effects on Kv channels, upregulating the current amplitude, while decreasing the voltage sensitivity. Interactions between PIP2 and the S4 segment or the S4-S5 linker in the closed state have been highlighted to explain the effects of PIP2 on voltage sensitivity. Here, we show that PIP2 preferentially interacts with the S4-S5 linker in the open-state KCNQ2 (Kv7.2) 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. Consistently, PIP2 exerts different effects on KCNQ2 relative to the Shaker and Kv1.2 channels; PIP2 up-regulates both the current amplitude and voltage sensitivity of the KCNQ2 channel. 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. In the closed state, PIP2 is anchored at the S2-S3 loop; upon channel activation, PIP2 interacts with the S4-S5 linker and is involved in channel gating.
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