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The ganglioside GM1 interacts with the serotonin 1A receptor via the sphingolipid binding domain.

Authors :
Prasanna X
Jafurulla M
Sengupta D
Chattopadhyay A
Source :
Biochimica et biophysica acta [Biochim Biophys Acta] 2016 Nov; Vol. 1858 (11), pp. 2818-2826. Date of Electronic Publication: 2016 Aug 20.
Publication Year :
2016

Abstract

Glycosphingolipids are minor yet essential components of eukaryotic cell membranes and are involved in a variety of cellular processes. Although glycosphingolipids such as GM1 have been previously reported to influence the function of G protein-coupled receptors (GPCRs), the molecular mechanism remains elusive. In this paper, we have explored the interaction of GM1 with the serotonin <subscript>1A</subscript> receptor, an important neurotransmitter receptor that belongs to the GPCR family. To examine the molecular basis of the interaction of GM1 with the serotonin <subscript>1A</subscript> receptor, we performed a series of coarse-grain molecular dynamics simulations of the receptor embedded in membrane bilayers containing GM1. Our results show that GM1 interacts with the serotonin <subscript>1A</subscript> receptor predominantly at the extracellular loop 1 and specifically at the sphingolipid binding domain (SBD). The SBD motif consists of a characteristic combination of aromatic, basic and turn-inducing residues, and is evolutionarily conserved in case of the serotonin <subscript>1A</subscript> receptor. The interaction of the SBD site with GM1 appears to stabilize a 'flip-out' conformation in which W102 of the extracellular loop 1 flips out from the central lumen of the receptor toward the membrane. The population of the 'flip-out' conformation is increased in the presence of cholesterol. Our data strongly suggest that a direct interaction between GM1 and the SBD site of the serotonin <subscript>1A</subscript> receptor may occur in vivo. In view of the reported role of GM1 and the serotonin <subscript>1A</subscript> receptor in neurodegenerative diseases, GM1-receptor interaction assumes significance in the context of malfunctioning of neuronal GPCRs under such conditions.<br /> (Copyright © 2016 Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
0006-3002
Volume :
1858
Issue :
11
Database :
MEDLINE
Journal :
Biochimica et biophysica acta
Publication Type :
Academic Journal
Accession number :
27552916
Full Text :
https://doi.org/10.1016/j.bbamem.2016.08.009