Eukaryotic cells contain phospholipids and nonphospholipids. The latter lack phosphodiester groups in their head group regions. Lipid-dependent gating of voltage-gated ion channels represents a steady-state energetic effect of nonphospholipids in favoring the resting state of voltage-sensor domains (VSDs) of the channels. It suggests adaptation of ion channels to lipid compositions in their native niche and significant roles of low-to-intermediate affinity lipid-binding sites at the channels. The nonphospholipids include glycoglycerolipids, glycosphingolipids, ceramides, cholesterol or cholesterol esters, diacylglycerol (DAG), fatty acids, cation lipids, etc. Change in relative ratios of phospholipids to nonphospholipids can shift the energetic levels of the VSDs and the gating of these channels, which in turn may alter excitability in certain cells. It is expected that reduced relative abundance of nonphospholipids / phospholipids in plasma membranes may change resting transmembrane potential or gating transitions of voltage-gated Na or K channels. The net results will be a change in action potential firing at least in certain areas of an excitable cell. Such changes in the central nervous system (CNS) are anticipated to affect brain functions and contribute to early-onset neurological phenotypes observed in patients carrying lipid metabolic defects. We will describe the basics of lipid-dependent gating and review its projected links to phenotypes of monogenic lipid metabolic defects and related changes of lipid composition in cell membranes as well as altered neuronal excitability in CNS. However, lack of high-resolution techniques to measure lipid composition around individual channels in cell membranes has been limiting the studies of direct connections between lipid redistribution caused by metabolic defects and altered ion channel activities. Potential solutions will be described for future studies
