Abstract
Voltage-gated ion channels generate dynamic ionic currents that are vital to the physiological functions of many tissues. These proteins contain separate voltage-sensing domains, which detect changes in transmembrane voltage, and pore domains, which conduct ions. Coupling of voltage sensing and pore opening is critical to the channel function and has been modeled as a protein–protein interaction between the two domains. Here, we show that coupling in Kv7.1 channels requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP
2
). We found that voltage-sensing domain activation failed to open the pore in the absence of PIP
2
. This result is due to loss of coupling because PIP
2
was also required for pore opening to affect voltage-sensing domain activation. We identified a critical site for PIP
2
-dependent coupling at the interface between the voltage-sensing domain and the pore domain. This site is actually a conserved lipid-binding site among different K
+
channels, suggesting that lipids play an important role in coupling in many ion channels.
