Role of Gangliosides in Peripheral Pain Mechanisms

Abstract

Gangliosides are abundantly occurring sialylated glycosphingolipids serving diverse functions in the nervous system. Membrane-localized gangliosides are important components of lipid microdomains (rafts) which determine the distribution of and the interaction among specific membrane proteins. Different classes of gangliosides are expressed in nociceptive primary sensory neurons involved in the transmission of nerve impulses evoked by noxious mechanical, thermal, and chemical stimuli. Gangliosides, in particular GM1, have been shown to participate in the regulation of the function of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1), a molecular integrator of noxious stimuli of distinct nature. Gangliosides may influence nociceptive functions through their association with lipid rafts participating in the organization of functional assemblies of specific nociceptive ion channels with neurotrophins, membrane receptors, and intracellular signaling pathways. Genetic and experimentally induced alterations in the expression and/or metabolism of distinct ganglioside species are involved in pathologies associated with nerve injuries, neuropathic, and inflammatory pain in both men and animals. Genetic and/or pharmacological manipulation of neuronal ganglioside expression, metabolism, and action may offer a novel approach to understanding and management of pain.

Antinociceptive Effects of Lipid Raft Disruptors, a Novel Carboxamido-Steroid and Methyl β-Cyclodextrin, in Mice by Inhibiting Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Channel Activation

“…Intraplantar injection of another components of lipid rafts, the ganglioside GT1b, produced nociceptive responses and enhanced formalin-induced nocifensive reactions. On the other hand, intraplantar injection of sialidase, which cleaves sialyl residues from gangliosides, attenuated these responses (Watanabe et al, 2011;Sántha et al, 2020). The flavanone isosakuranetin blocked PS-induced Ca 2+ -influx in DRG neurons and significantly attenuated the noxious heat-and PS-induced pain sensation in mice (Straub et al, 2013).…”

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

“…Available experimental evidence indicates that ganglioside GM1 is significantly implicated in the mediation of the neurotrophic effect of NGF in primary sensory neurons [144]. TRPV1 receptors are associated with and regulated by GM1, an important constituent of membrane lipid rafts [145][146][147]. Since InsRs are recruited upon ligand binding to membrane lipid microdomains [148], an interaction of the InsR with the TRPV1 receptor at the lipid raft domains of the plasma membrane cannot be excluded.…”

ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities

“…Sequence alignment and molecular modeling predict an interaction of SARS-CoV-2 S (243–302 aa) with sialic acids similar to the one observed for MERS-CoV S ( Park et al, 2019 ; Milanetti et al, 2020 ; Vandelli et al, 2020 ). Further molecular dynamic simulation of SARS-CoV-2 S interaction with the ganglioside GM1, a glycosphingolipid containing one or more sialic acid residues ( Fantini et al, 2020 ; Sántha et al, 2020 ; Kuhn and Wiegandt, 1963 ), points to the formation of a trimolecular complex between a ganglioside binding domain (111–162 aa) and two GM1 molecules. Although these studies propose distinct regions of interaction of S with sialic acids, they point to a model in which SARS-CoV-2 could bind to ganglioside regions exposed at the cell membrane potentially favoring the subsequent interaction of the RBD with ACE2 ( Figure 1 ).…”