Key result
Molecular dynamics simulations show that in the presence of KCNE1, two PIP2 lipids are necessary to stabilize each state of the IKS channel complex, forming a tourniquet around the pore.
Why the study?
PIP2 is crucial for coupling the voltage sensor to the pore of KV7.1 channels forming the IKS current, but the molecular mechanisms governing KCNE1 modulation of IKS by PIP2 remained to be defined.
This computational study provides key molecular insights into how PIP2 and KCNE1 modulate IKS channels, suggesting a potential common mechanism for auxiliary subunit modulation of ion channels.
Does not alter clinical management of IKS-related arrhythmias; leaves open KCNE1-PIP2 interactions as a hypothesis-generating research target.
The phosphatidyl-inositol-4,5-bisphosphate (PIP2) lipid has been shown to be crucial for the coupling between the voltage sensor and the pore of the potassium voltage-gated KV7 channel family, especially the KV7.1 channel. Expressed in the myocardium membrane, KV7.1 forms a complex with KCNE1 auxiliary subunits to generate the IKS current. Here we present molecular models of the transmembrane region of this complex in its three known states, namely the Resting/Closed (RC), the Intermediate/Closed (IC), and the Activated/Open (AO), robustness of which is assessed by agreement with a range of biophysical data. Molecular Dynamics (MD) simulations of these models embedded in a lipid bilayer including phosphatidyl-inositol-4,5-bisphosphate (PIP2) lipids show that in presence of KCNE1, two PIP2 lipids are necessary to stabilize each state. The simulations also show that KCNE1 interacts with both PIP2 binding sites, forming a tourniquet around the pore and preventing its opening. The present investigation provides therefore key molecular elements that govern the role of PIP2 in KCNE1 modulation of IKS channels, possibly a common mechanism by which auxiliary KCNE subunits might modulate a variety of other ion channels.
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Kongmeneck et al. (2023) studied this question. Molecular Dynamics (MD) simulations was evaluated on Stabilization of KV7.1-KCNE1 complex states. Molecular dynamics simulations show that in the presence of KCNE1, two PIP2 lipids are necessary to stabilize each state of the IKS channel complex, forming a tourniquet around the pore.
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