4.5 Article

Conductance properties of the inwardly rectifying channel, Kir3.2: Molecular and Brownian dynamics study

期刊

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
卷 1828, 期 2, 页码 471-478

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2012.09.022

关键词

GIRK2; Kir3.2; Inwardly rectifying potassium channel; Conductance property; Molecular dynamics; Brownian dynamics

资金

  1. Australian Research Council
  2. National Health and Medical Council
  3. NCI National Facility at the Australian National University

向作者/读者索取更多资源

Using the recently unveiled crystal structure, and molecular and Brownian dynamics simulations, we elucidate several conductance properties of the inwardly rectifying potassium channel, Kir3.2, which is implicated in cardiac and neurological disorders. We show that the pore is closed by a hydrophobic gating mechanism similar to that observed in Kv1.2. Once open, potassium ions move into, but not out of, the cell. The asymmetrical current-voltage relationship arises from the lack of negatively charged residues at the narrow intracellular mouth of the channel. When four phenylalanine residues guarding the intracellular gate are mutated to glutamate residues, the channel no longer shows inward rectification. Inward rectification is restored in the mutant Kir3.2 when it becomes blocked by intracellular Mg2+. Tertiapin, a polypeptide toxin isolated from the honey bee, is known to block several subtypes of the inwardly rectifying channels with differing affinities. We identify critical residues in the toxin and Kir3.2 for the formation of the stable complex. A lysine residue of tertiapin protrudes into the selectivity filter of Kir3.2, while two other basic residues of the toxin form hydrogen bonds with acidic residues located just outside the channel entrance. The depth of the potential of mean force encountered by tertiapin is -16.1 kT, thus indicating that the channel will be half-blocked by 0.4 mu M of the toxin. (C) 2012 Elsevier B.V. All rights reserved.

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