Regulation of Membrane Calcium Transport Proteins by the Surrounding Lipid Environment

Abstract

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.

Interplay Between Plasma Membrane Lipid Alteration, Oxidative Stress and Calcium-Based Mechanism for Extracellular Vesicle Biogenesis From Erythrocytes During Blood Storage

“…For instance, cholesterol-enriched domains and cholesterol content were decreased very rapidly and simultaneously, which could be highly detrimental for RBCs through: (i) lower RBC deformability and increased elimination in the spleen, since cholesterol deficiency causes impaired RBC osmotic stability during ex vivo erythropoiesis ( Bernecker et al, 2019 ) and cholesterol-enriched domains are necessary for the formation of high curvature areas during RBC deformation ( Leonard et al, 2017 ); (ii) PS exposure and subsequent RBC elimination by macrophages, as revealed by the direct correlation between cholesterol content and the extent of PS exposure; and (iii) the increase of membrane rigidity, as revealed by Laurdan and AFM. Those modifications could in turn affect the dynamics of the low RBC curvature-associated domains enriched in GM1 or sphingomyelin, precluding calcium exchanges at the RBC surface ( Conrard et al, 2018 ; Conrard and Tyteca, 2019 ). Hence, ceramide-enriched domains were lost upon storage, which could be favorable for the RBC as ceramide is known to be involved in several signaling pathways including cell death ( Dinkla et al, 2012 ).…”

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

“…Early simulations of membrane proteins were performed without membrane embedding, but today accurate membrane modeling has allowed for the simulation of realistic cellular membrane environments [357,358]. In vitro data on membrane thickness, curvature, fluidity [359], and surface tension [360] has enabled accurate modeling of ligand binding and the corresponding downstream activation of the signaling proteins [361,362]. Furthermore, multiscale MD simulations combining atomistic and coarse-grained MD can also give structural and functional insights into important protein-lipid interactions, protein oligomerization, clustering, and crowding [363].…”

Aberrant Membrane Composition and Biophysical Properties Impair Erythrocyte Morphology and Functionality in Elliptocytosis

“…This is in agreement with the suppression of PIEZO1 activation in myoblasts upon altered PS membrane flip-flop and lysoPS membrane insertion [ 51 ]. Besides curvature alteration, lysoPS specifically increased the abundance of GM1-enriched domains, previously suggested to contribute to Ca 2+ influx through PIEZO1 [ 10 , 52 ]. This hypothesis is supported by the specific excellent correlation between GM1-enriched domain abundance in RBCs at resting state and the Ca 2+ influx through PIEZO1 upon RBC mechanical activation, revealing that the higher the domain abundance, the lower their ability to induce Ca 2+ influx ( Figure S12C ).…”

“…The implication of those mechanisms in pEl RBCs remains nevertheless to be tested. A non-mutually exclusive alternative mechanism is provided by the alteration of sphingomyelin-enriched domains, previously suggested to participate to Ca 2+ efflux through PMCA [ 10 , 52 ]. This hypothesis is supported by the specific correlation between sphingomyelin-enriched domain abundance in RBCs at resting state and the extent of Ca 2+ efflux through PMCA, revealing that the higher the domain abundance, the lower their ability to induce Ca 2+ efflux through PMCA ( Figure S12E ).…”