E224G Regulation of the PIP$_{2}$-Induced Gating Kinetics of Kir2.1 Channels

doi:10.1088/0256-307X/34/1/016102

Chin. Phys. Lett.

2017, Vol. 34

Issue (1): 016102 DOI: 10.1088/0256-307X/34/1/016102

CONDENSED MATTER: STRUCTURE, MECHANICAL AND THERMAL PROPERTIES

E224G Regulation of the PIP$_{2}$-Induced Gating Kinetics of Kir2.1 Channels

Shu-Xi Ren¹, Jun-Wei Li¹, Su-Hua Zhang¹, D. E. Logothetis², Hai-Long An^1**, Yong Zhan^1**

¹Key Laboratory of Molecular Biophysics of Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401
²Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Virginia, USA

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Shu-Xi Ren, Jun-Wei Li, Su-Hua Zhang et al 2017 Chin. Phys. Lett. 34 016102

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Abstract As a member of the inwardly rectifying K$^{+}$ channel (Kir) family, Kir2.1 allows K$^{+}$ to influx the cell more easily than to efflux, a biophysical phenomenon named inward rectification. The function of Kir2.1 is to set the resting membrane potential and modulate membrane excitability. It has been reported that residue E224 plays a key role in regulating inward rectification. The mutant Kir2.1 (E224G) displays weaker inward rectification than the WT channel. Gating of Kir2.1 depends on the membrane lipid, PIP$_{2}$, such that the channel gates are closed in the absence of PIP$_{2}$. Here we perform electrophysiological and computational approaches, and demonstrate that E224 also plays an important role in the PIP$_{2}$-dependent activation of Kir2.1 in addition to its influence on inward rectification. The E224G mutant takes 4.5 times longer to be activated by PIP$_{2}$. To probe the mechanism by which E224G slows the channel opening kinetics, we perform targeted molecular dynamics simulations and find that the mutant weakens the interactions between CD-loop and C-linker (H221-R189) and the adjacent G-loops (R312-E303) which are thought to stabilize the open state of the channel in our previous work. These data provide new insights into the regulation of Kir2.1 channel activity and suggest that a common mechanism may be involved in the distinct biophysical processes, such as inward rectification and PIP$_{2}$-induced gating.

Received: 05 August 2016 Published: 29 December 2016

PACS:	61.80.Lj	(Atom and molecule irradiation effects)
	87.16.dp	(Transport, including channels, pores, and lateral diffusion)
	87.16.Vy	(Ion channels)

Fund: Supported by the National Natural Science Foundation for Distinguished Young Scholars of Hebei Province under Grant Nos C2015202340 and C2013202244, the Foundation for Outstanding Talents of Hebei Province under Grant No C201400305, the National Natural Science Foundation of China under Grant Nos 11247010, 11175055, 11475053, 11347017, 31400711 and 11647121, the NIH R01 under Grant No HL059949-18, the Foundation for the Science and Technology Program of Higher Education Institutions of Hebei Province under Grant No QN2016113, and the Scientific Innovation Fund for Excellent Young Scientists of Hebei University of Technology under Grant No 2015010.

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https://cpl.iphy.ac.cn/10.1088/0256-307X/34/1/016102 OR https://cpl.iphy.ac.cn/Y2017/V34/I1/016102

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	Shu-Xi Ren
	Jun-Wei Li
	Su-Hua Zhang
	D. E. Logothetis
	Hai-Long An
	Yong Zhan

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