It is worth noting that NGF-, insulin-like growth factor-1 (IGF-1)- and insulin-induced sensitization of the TRPV1 receptor to capsaicin [138] has also been shown to be mediated by translocation and insertion of intracellular TRPV1 into the plasma membrane [139,140]

It is worth noting that NGF-, insulin-like growth factor-1 (IGF-1)- and insulin-induced sensitization of the TRPV1 receptor to capsaicin [138] has also been shown to be mediated by translocation and insertion of intracellular TRPV1 into the plasma membrane [139,140]. 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. could affect the integrity of lipid rafts, independently of the action of myriocin on glycosphingolipids, including gangliosides. Indeed, several studies demonstrated that treatment of sensory ganglion cell cultures or TRPV1 expressing cells with sphingomyelinase, which cleaves sphingomyelin but not glycoconjugated sphingolipids, profoundly reduced TRPV1 (and TRPA1) activation [133,135]. Data obtained using sphingomyelinase treatment suggest, that besides cholesterol and gangliosides, the sphingomyelin level in the membrane rafts is also critical in maintaining the integrity and functions of raft-embedded molecular complexes including the operation of TRP channels [133,135]. It cannot be excluded, however, that manipulation of the sphingomyelin level, and consequently, ceramide concentration in the plasma membrane after sphingomyelinase treatment could indirectly influence the concentration (and distribution) of glycosphingolipids as well, but detailed description on the dynamics of changes in the membrane lipid composition remains to be clarified. Importantly, these studies disclosed Rabbit Polyclonal to GABBR2 that apart from activation of TRPV1, the activation of other nociceptive transducer molecules, such as TRPA1 and the effects of endogenous/exogenous algogenic substances which activate PJ 34 hydrochloride them could be affected by disintegration of membrane lipid rafts and/or manipulation of the metabolism of raft components, including probably gangliosides as well [135]. The findings that the TRPA1 agonist, allyl isothiocyanate-induced cobalt uptake was significantly reduced after chronic d-PDMP treatment demonstrate that activation of this nociceptive ion channel is also dependent on membrane gangliosides [136]. The association of TRPV1 with the specific membrane protein caveolin-1, which plays a pivotal role in endocytotic processes has also been demonstrated. Experiments on a CHO cell-based expression system demonstrated restricted mobility and association of TRPV1 with caveolin-1 [137]. Importantly, exposure of TRPV1-expressing cells to vanilloid receptor agonist resiniferatoxin resulted in the translocation of TRPV1 into cytoplasmic caveolar vesicles. This observation strongly suggested that association of TRPV1 with caveolin-1 and the caveolin-1-dependent internalization of TRPV1 may be a possible mechanism of vanilloid agonist-induced desensitization of the TRPV1 receptor [137]. It is worth noting that NGF-, insulin-like growth factor-1 (IGF-1)- and insulin-induced sensitization of the TRPV1 receptor to capsaicin [138] has also been shown to be mediated by translocation and insertion of intracellular TRPV1 into the plasma membrane [139,140]. Both NGF and insulin/IGF signaling is critically dependent on the functions of lipid rafts [131,141], and in the case of insulin on the caveolar membrane [142,143]. The substantial role of the stimulus intensity-dependent internalization and dynamic recycling of membrane-bound TRPV1 has been recently confirmed and supplemented with further details demonstrating the importance of synaptotagmin 1 and 7 in the mechanism of capsaicin-induced tachyphylaxis PJ 34 hydrochloride and recovery [144]. 7. Conclusion and Perspectives Experimental data on the role of gangliosides in somatosensation are relatively sparse PJ 34 hydrochloride as compared to the vast literature on the effects of these glycosphingolipids on the central nervous system. However, investigations into the mechanisms of somatosensory functions, in particular transmission of nociceptive impulses have revealed that glycosphingolipids, including gangliosides may interfere with the function of primary sensory neurons through diverse interactions with membrane receptors/ion channels, lipid rafts, membrane, and intracellular signaling pathways, cellular calcium homeostasis, and immune mechanisms. Ganglioside GM1 plays an important role in the NGF-dependent regulation of the expression and activation of nociceptive ion channels, such as the archetypal TRPV1 receptor. Major ganglioside species GM1, GD1a, GD1b, and GT1b are involved in the modulation of spinal and trigeminal nociception either by contributing to the functional organization of membrane lipid rafts or linking membrane proteins to membrane and intracellular signaling pathways. Importantly, alterations in cellular ganglioside homeostasis may.