Chemistry Reference
In-Depth Information
Info Box 1
Gangliosides modulate receptors, enzymes, ion channels and other proteins
through direct association or indirectly through signaling sequences - triggered
by cross-linking. GM1 has been the most studied from this standpoint, several
examples of which follow:
•
The tropomyosin -related kinase A receptor for nerve growth factor is tightly
associated with GM1 and fails to fulfi ll its functional role - stimulation of
neuronal differentiation - in its absence [T. Mutoh
et al.
Stable transfection
of GM1 synthase gene into GM1- defi cient NG108 - 15 cells, CR - 72 cells,
rescues the responsiveness of Trk-neurotrophin receptor to its ligand, NGF.
Neurochem Res
2002;
27
, 801 - 806].
•
Opioid receptors are converted by GM1 from inhibitory to excitatory mode,
leading to opioid tolerance and dependence [G. Wu
et al.
Interaction of the
-opioid receptor with GM1 ganglioside: conversion from inhibitory to excit-
atory mode.
Mol Brain Res
1997;
44
, 341 - 346].
•
A sodium-calcium exchanger in the nuclear envelope is tightly associated
with and potentiated by GM1 [X. Xie
et al.
Potentiation of a sodium-calcium
exchanger in the nuclear envelope by nuclear GM1 ganglioside.
J Neurochem
2002;
81
, 1185 - 1195].
•
Cross - linking of GM1 leads to TRPC5 Ca
2+
channel activation - an example
of 'modulation at a distance' [G. Wu
et al.
Induction of calcium infl ux through
TRPC5 channels by cross-linking of GM1 ganglioside associated with
δ
1
integrin initiates neurite outgrowth.
J Neurosci
2007;
27
, 7447 - 7458]. A
human lectin is capable to act as natural GM1 cross-linking agent [J. Wang
et al.
Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T
cell activity involving TRPC5 channel activation: possible role in suppressing
experimental autoimmune encephalomyelitis.
J Immunol
2009;
182
, 4036 -
4045]. The roles of galectins-1 and -3 as GM1 receptors in neuroblastoma
cells are described in Chapter 25.2 .
•
GM1 in the endoplasmic reticulum induces Ca
2+
release via the endoplasmic
reticulum stress response system [A. Tessitore
et al.
GM1 - ganglioside -
mediated activation of the unfolded protein response causes neuronal death
in a neurodegenerative gangliosidosis.
Mol Cell
2004;
15
, 753 - 766].
•
GM1 binds to calmodulin and inhibits calmodulin- dependent enzymes [K.
Higashi, T. Yamagata. Mechanism for ganglioside- mediated modulation of
calmodulin-dependent cyclic nucleotide phosphodiesterase activity through
binding of gangliosides to calmodulin and the enzyme.
J Biol Chem
1992;
267
, 9839-9843]. Inhibition of nitric oxide synthase, a calmodulin- dependent
enzyme, was proposed as a mechanism for the neuroprotective effect of GM1
(and other gangliosides) [T.M. Dawson
et al.
Neuroprotective effects of gan-
gliosides may involve inhibition of nitric oxide synthase.
Ann Neurol
1995;
37
, 115 - 118].
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