Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 49, Pages 18934-18948Publisher
ELSEVIER
DOI: 10.1074/jbc.RA119.010047
Keywords
phosphoinositide; G protein; gating; potassium channel; molecular dynamics; molecular modeling; membrane protein; allosteric regulation; transmembrane domain; channel activation; G?? dimer; GIRK2 channel; intracellular Na+; molecular dynamics simulations; PIP2
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Funding
- Foundation of Fujian Educational Committee [JA13236]
- Xiamen University of Technology [E201300100]
- National Institutes of Health [NIH R01 HL059949-22]
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G protein?gated inwardly rectifying K+ (GIRK) channels belong to the inward-rectifier K+ (Kir) family, are abundantly expressed in the heart and the brain, and require that phosphatidylinositol bisphosphate is present so that intracellular channel-gating regulators such as G?? and Na+ ions can maintain the channel-open state. However, despite high-resolution structures (GIRK2) and a large number of functional studies, we do not have a coherent picture of how G?? and Na+ ions control gating of GIRK2 channels. Here, we utilized computational modeling and all-atom microsecond-scale molecular dynamics simulations to determine which gates are controlled by Na+ and G?? and how each regulator uses the channel domain movements to control gate transitions. We found that Na+ ions control the cytosolic gate of the channel through an anti-clockwise rotation, whereas G?? stabilizes the transmembrane gate in the open state through a rocking movement of the cytosolic domain. Both effects alter the way in which the channel interacts with phosphatidylinositol bisphosphate and thereby stabilizes the open states of the respective gates. These studies of GIRK channel dynamics present for the first time a comprehensive structural model that is consistent with the great body of literature on GIRK channel function.
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