An exposed carboxyl group on sialic acid is essential for gangliosides to inhibit calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase: relevance to gangliosidoses.
We previously observed that gangliosides GM2, GM1, and GM3 inhibit Ca2+-uptake via the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) in neurons and in brain microsomes. We now systematically examine the effect of various gangliosides and their analogs on Ca2+-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 (CH2OH), a methyl ester (COOCH3) or a taurine-conjugated amide (CONHCH2CH2SO3H) 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.
Ginzburg
Luba
L
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Li
Su-Chen
SC
Li
Yu-Teh
YT
Futerman
Anthony H
AH
D000818:Animals; D001921:Brain / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005732:Gangliosides / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D008861:Microsomes / Q000648:ultrastructure; D019158:N-Acetylneuraminic Acid / Q000494:pharmacology*; D009282:Naphthalenesulfonates; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology*; D013053:Spectrophotometry / Q000379:methods
D005732:Gangliosides; D009282:Naphthalenesulfonates; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019158:N-Acetylneuraminic Acid; C016238:antipyrylazo III; D002118:Calcium