Abstract
Voltage-gated potassium (Kv) channels contain voltage-sensing (VSD) and pore-gate (PGD) structural domains. During voltage-dependent gating, conformational changes in the two domains are coupled giving rise to voltage-dependent opening of the channel. In addition to membrane voltage, KCNQ (Kv7) channel opening requires the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Recent studies suggest that PIP2 serves as a cofactor to mediate VSD-PGD coupling in KCNQ1 channels. In this review, we put these findings in the context of the current understanding of voltage-dependent gating, lipid modulation of Kv channel activation, and PIP2-regulation of KCNQ channels. We suggest that lipid-mediated coupling of functional domains is a common mechanism among KCNQ channels that may be applicable to other Kv channels and membrane proteins.
Highlights
Lipids define the physical and chemical environment of voltagegated ion channels, yet most of the literature in the ion channel field considers only the channel protein and its proteinacious interacting partners
We have recently developed an assay to directly detect the voltage-sensing domains (VSDs)-pore-gate domain (PGD) coupling in KCNQ1 by using a mutation to lock the PGD in the open conformation and measuring the impact of PGD opening on VSD activation using voltage clamp fluorometry (VCF) (Zaydman et al, 2013)
We found that the coupling between the activated-state of the VSD and the open-state of the PGD requires binding of PIP2 at the VSD-PGD interface (Figure 4), thereby providing functional evidence that lipids play a role in VSD-PGD coupling
Summary
Lipids define the physical and chemical environment of voltagegated ion channels, yet most of the literature in the ion channel field considers only the channel protein and its proteinacious interacting partners. All these channels are voltage-gated, they all require PIP2 to open, and it appears that they all share a conserved PIP2 binding site at the VSD-PGD interface (see below).
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