Cholesterol is ubiquitous in plasma membranes, accounting for up to 50% of the lipid mass22. Changes in brain cholesterol are implicated in numerous neurodegenerative diseases, such as Alzheimer’s, Huntington’s, Parkinson’s, and Niemann-Pick disease62. Cholesterol metabolism and utilization in the brain is significantly different than the rest of the body. Although the brain only makes up 2-5% of the body mass, almost 25% of the total body cholesterol resides in the brain63. Moreover, cholesterol degradation in the brain is low. An increase of cholesterol in the brain has been reported to decrease the firing rate in hippocampal neurons, suggesting it may reduce excitability64. Notably, some types of GIRK channels are localized in lipid rafts, which are enriched in cholesterol65, 66. Thus, changes in membrane cholesterol content may alter the basal activity of neuronal GIRK channels. Consistent with this, Bukiya et al. (2017) reported that cholesterol enrichment increased baclofen-induced, tertiapin-inhibited GIRK-like currents in hippocampal neurons. Similarly, cholesterol (33%) enhanced the basal activity of a constitutively-active mutant GIRK2 channel43.
