Cholesterol and Cholesterol-Derived Molecules Differentially Modulate Neuronal Kv7.2/7.3 Channels

Abstract

Kv7 potassium channels generate slowly activating, non-inactivating outward potassium currents and are critical regulators of cellular excitability. While cholesterol is known to modulate multiple ion channels, its concentration-dependent effects and the influence of cholesterol-derived molecules on Kv7 channels remain insufficiently characterized. In this study, we investigated the effects of cholesterol and cholesterol-derived molecules, including steroid hormones and chemically modified imidazolium-based cholesterol derivatives (CHIMs) on Kv7.2/7.3 channels heterologously expressed in HEK293FT cells using conventional whole-cell patch-clamp recordings. Application of high cholesterol concentrations (1 mM) significantly reduced Kv7.2/7.3 current amplitudes over a wide range of potentials without changing voltage-dependent current characteristics. CHIMs also reduced currents, whereas a fluorescent derivative, CHIM-L-NBD, unexpectedly enhanced Kv7.2/7.3 currents. In contrast, the NBD moiety alone had no effect. Progesterone and 17β-estradiol inhibition of Kv7.2/7.3 currents was most evident at strongly depolarized potentials. For progesterone this was associated with a change in the slope of the activation curve. These findings demonstrate that Kv7.2/7.3 channels respond differentially to structural modifications of cholesterol and to steroid hormones thereby suggesting that different cholesterol-derived molecules may serve as tool compounds with potentially opposing modulatory effects on Kv7.2/7.3 channels.