The ether-à-go-go1 (EAG1, Kv10.1) K channel is a member of the voltage-gated K channel family mainly expressed in the central nervous system and cancer cells. Membrane lipids regulate several voltage-gated K channels but their influence on EAG1 channels has been poorly explored. Here we have studied the regulation of hEAG1 channels by phosphatidylinositol 4,5-bisfofate (PIP) by using different strategies to manipulate the levels of this lipid, and the patch clamp technique. We found that depletion of endogenous PIP by activation of the voltage-sensing phosphatase from Danio rerio (Dr-VSP) or the human muscarinic type-1 receptor (hM1R) inhibits hEAG1 currents; however, the application of exogenous PIP to increase the level of this lipid on the plasma membrane, also induced an inhibition of hEAG1. In summary, our results indicate that PIP have dual effects on hEAG1 channels and its action as activator or inhibitor depends on its initial level on the plasma membrane.
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