Dual regulation of hEAG1 channels by phosphatidylinositol 4,5-bisphosphate.

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 (PIP₂) by using different strategies to manipulate the levels of this lipid, and the patch clamp technique. We found that depletion of endogenous PIP₂ 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 PIP₂ to increase the level of this lipid on the plasma membrane, also induced an inhibition of hEAG1. In summary, our results indicate that PIP₂ 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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