Similar to its effects on brain GIRK2 channels, cholesterol enhances acetylcholine activated potassium (KACh) channels in the heart, which are composed of GIRK1 and GIRK4 subunits23, 27. Interestingly, this effect was proposed to be independent of Gβγ but with little change in the apparent PIP2 affinity23. In these experiments, the relative association of PIP2 with GIRK1/GIRK4 heteromeric or GIRK4* homomeric channels was inferred from measuring the rate of current inhibition following activation of a PIP2-depleting phosphatase23. The rate was similar in the absence and presence of cholesterol23. By contrast, we find that cholesterol activates the neuronal GIRK2 channel activity by increasing the apparent association with PIP2 in the absence of Gβγ subunits. Whether this difference in PIP2 dependence is unique to GIRK2 remains to be determined.
