Modulation of Neuronal GIRK 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) currents in atrial myocytes. Here we focus on neuronal GIRK channels, and determine the effect of cholesterol on their function. Several GIRK subunits are expressed in the hippocampus: GIRK1, GIRK2a, GIRK2c and GIRK3. Among these, GIRK2 may be expressed as a homomer or as a heteromer with GIRK1 and/or GIRK3, both of which do not express as homomers in the plasma membrane. We first studied the effect of cholesterol on a pore mutant of GIRK2, GIRK2^ (GIRK2_E152D). We show that when GIRK2^ is expressed in Xenopus oocytes, its currents are up‐regulated by cholesterol. Next, using planar lipid bilayers we demonstrate that cholesterol significantly increases the open probability of the GIRK2^ channels. No apparent change was observed in the unitary current amplitude. Finally, we show that in‐vitro cholesterol enrichment of freshly isolated hippocampal neurons results in a strong increase in physiological GIRK currents. These findings point at cholesterol as a critical lipid regulator of GIRK channel activity in the brain.