Sphingolipids modulate the function of human serotonin 1A receptors: Insights from sphingolipid-deficient cells

Abstract

Sphingolipids are essential components of eukaryotic cell membranes and are known to modulate a variety of cellular functions. It is becoming increasingly clear that membrane lipids play a crucial role in modulating the function of integral membrane proteins such as G protein-coupled receptors (GPCRs). In this work, we utilized LY-B cells, that are sphingolipid-auxotrophic mutants defective in sphingolipid biosynthesis, to monitor the role of cellular sphingolipids in the function of an important neurotransmitter receptor, the serotonin receptor. Serotonin receptors belong to the family of GPCRs and are implicated in behavior, development and cognition. Our results show that specific ligand binding and G-protein coupling of the serotonin receptor exhibit significant enhancement under sphingolipid-depleted conditions, which reversed to control levels upon replenishment of cellular sphingolipids. In view of the reported role of sphingolipids in neuronal metabolism and pathogenesis of several neuropsychiatric disorders, exploring the role of serotonin receptors under conditions of defective sphingolipid metabolism assumes relevance, and could contribute to our overall understanding of such neuropsychiatric disorders. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.

Sphingolipids in plants: a guidebook on their function in membrane architecture, cellular processes, and environmental or developmental responses

“…This in situ observation fits particularly well with in vitro membrane reconstitution assays using GUVs containing phospholipids and ceramides where SLs with acyl‐chain 24 atoms of carbon form interdigitated gel phase and membrane tubules, in contrast to SLs with acyl‐chain length of 18 atoms of carbon [110]. Finally, the finding that SLs directly interact with a specific transmembrane domain of a subset of proteins, especially the seven transmembrane domains proteins of the G‐protein coupled receptors, opens a new exiting avenue for future research on the regulatory role of the SLs‐chains in membrane functioning [111–113].…”

“…protein coupled receptors, opens a new exiting avenue for future research on the regulatory role of the SLs-chains in membrane functioning [112][113][114] . 116,124,128 .…”

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

“…Specific binding of receptor agonists to the human serotonin 1A receptor was markedly reduced when sphingomyelin in the membrane surrounding the receptor was converted to ceramide by sphingomyelinase with no significant perturbation to the membrane order [ 155 ]. This effect on agonist binding was found to be reversible on replenishment of sphingolipids [ 156 ]. Prompted by the observed sensitivity of serotonin 1A towards sphingolipids, amino acid sequence analysis led to the proposal of a putative sphingolipid binding domain (SBD) [ 157 ], which in parts overlaps with the cholesterol CRAC motif on TM5 [ 158 ].…”

Imaging of intermittent lipid-receptor interactions reflects changes in live cell membranes upon agonist-receptor binding

“…Although many underlying mechanisms have been clarified by biochemical and biophysical investigations, additional mechanisms remain to be revealed to explain the broad, yet precise and efficient, intracellular actions of GPCRs. Increasing evidence suggest that interactions with membrane lipids play a major role in modulating the function of GPCRs 2–4 . Such interactions include binding of specific lipids, in particular cholesterol, to specific sites on the GPCRs, formation of domains with specific lipid compositions around the GPCRs 5 , lipid selectivity to the protein 6 , or localized deformations of the membrane bilayer around the proteins 7 .…”