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An exposed carboxyl group on sialic acid is essential for gangliosides to inhibit calcium uptake via the sarco/endoplasmic reticulum Ca 2+ ‐ATPase: relevance to gangliosidoses
Author(s) -
Ginzburg Luba,
Li SuChen,
Li YuTeh,
Futerman Anthony H.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04983.x
Subject(s) - endoplasmic reticulum , serca , ganglioside , chemistry , biochemistry , ceramide , sialic acid , sphingosine , atpase , enzyme , receptor , apoptosis
We previously observed that gangliosides GM2, GM1, and GM3 inhibit Ca 2+ ‐uptake via the sarco/endoplasmic reticulum Ca 2+ ‐ATPase (SERCA) in neurons and in brain microsomes. We now systematically examine the effect of various gangliosides and their analogs on Ca 2+ ‐uptake via SERCA and demonstrate that an exposed carboxyl group on the ganglioside sialic acid residue is required for inhibition. Thus, asialo‐GM2 and asialo‐GM1 have no inhibitory effect, and modifications of the carboxyl group of GM1 and GM2 into a hydroxymethyl residue (CH 2 OH), a methyl ester (COOCH 3 ) or a taurine‐conjugated amide (CONHCH 2 CH 2 SO 3 H) drastically diminish their inhibitory activities. We also demonstrate that the saccharides must be attached to a ceramide backbone in order to inhibit SERCA as the ceramide‐free ganglioside saccharides only inhibit SERCA to a minimal extent. Finally, we attempted to use the ceramide‐free ganglioside saccharides to antagonize the effects of the gangliosides on SERCA; although some reversal was observed, the inhibitory effects of the gangliosides were not completely abolished.