Modulation of Neuronal Kir3 Channels by Cholesterol

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In recent years, cholesterol emerged as a major regulator of ion channel function. The most common effect of cholesterol on ion channels is a decrease in channel activity. We have recently shown that unexpectedly cholesterol enrichment up-regulates G-protein gated inwardly rectifying potassium (GIRK or Kir3) activity in atrial myocytes.Here we focus on neuronal Kir3 channels, and determine the effect of cholesterol on their function. Several Kir3 subunits are expressed in the hippocampus: Kir3.1, Kir3.2a, Kir3.2c and Kir3.3. Among these, Kir3.2 may be expressed as a homomer or as a heteromer with Kir3.1 and/or Kir3.3, both of which do not express as homomers in the plasma membrane.We first studied the effect of cholesterol on a pore mutant of Kir3.2 that increases its membrane expression and activity, Kir3.2∧ (Kir3.2_E152D). We show that when Kir3.2∧ was expressed in Xenopus oocytes, the resulting current was up-regulated by in vitro cholesterol enrichment of the oocyte membrane. Next, using planar lipid bilayers we demonstrate that cholesterol significantly increased the open probability of the Kir3.2∧ channels. No change was observed in the unitary conductance. Most importantly, we show that also in vitro cholesterol enrichment of freshly isolated hippocampal pyramidal neurons resulted in a strong increase in physiological Kir3 currents. These findings indicate that cholesterol plays a critical role in modulating neuronal Kir3 channels.