Numerous ion channels undergo palmitoylation, a lipid modification process. Moreover, a significant subset of ion channels demonstrate a direct affinity for cholesterol binding. The regulation of ion channels by cholesterol can stem from both direct binding interactions and an indirect influence, facilitated by the localization of palmitoylated residues within lipid rafts. It's important to note that these two mechanisms are not mutually exclusive; they can concurrently contribute to the modulation of ion channel activity and localization.
The spatial arrangement of an ion channel can profoundly impact its activation potential. Proposed mechanisms for this phenomenon encompass alterations in membrane thickness and the concentration of lipid molecules critical for signaling. One instance of this is observed in TREK-1 channels, which transition between lipid rafts and PIP2 domains, where they interact with an activating lipid. Similarly, Kir2.1 channels experience inhibition due to cholesterol while being activated by PIP2. Consequently, a transition from cholesterol-enriched GM1 to PIP2-rich domains is anticipated to trigger channel activation. Conversely, the scenario is opposite for nAChR, which responds positively to cholesterol, eliciting its activation.