Regulation of Membrane Calcium Transport Proteins by the Surrounding Lipid Environment

Calcium ions (Ca²⁺) are major messengers in cell signaling, impacting nearly every aspect of cellular life. Those signals are generated within a wide spatial and temporal range through a large variety of Ca²⁺ channels, pumps, and exchangers. More and more evidences suggest that Ca²⁺ exchanges are regulated by their surrounding lipid environment. In this review, we point out the technical challenges that are currently being overcome and those that still need to be defeated to analyze the Ca²⁺ transport protein-lipid interactions. We then provide evidences for the modulation of Ca²⁺ transport proteins by lipids, including cholesterol, acidic phospholipids, sphingolipids, and their metabolites. We also integrate documented mechanisms involved in the regulation of Ca²⁺ transport proteins by the lipid environment. Those include: (i) Direct interaction inside the protein with non-annular lipids; (ii) close interaction with the first shell of annular lipids; (iii) regulation of membrane biophysical properties (e.g., membrane lipid packing, thickness, and curvature) directly around the protein through annular lipids; and (iv) gathering and downstream signaling of several proteins inside lipid domains. We finally discuss recent reports supporting the related alteration of Ca²⁺ and lipids in different pathophysiological events and the possibility to target lipids in Ca²⁺-related diseases.