The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content.
Synaptophysin interacts with synaptobrevin in membranes of adult small synaptic vesicles. The synaptophysin/synaptobrevin complex promotes synaptobrevin to built up functional SNARE complexes thereby modulating synaptic efficiency. Synaptophysin in addition is a cholesterol-binding protein. Depleting the membranous cholesterol content by filipin or beta-methylcyclodextrin (beta-MCD) decreased the solubility of synaptophysin in Triton X-100 with less effects on synaptobrevin. In small synaptic vesicles from rat brain the synaptophysin/synaptobrevin complex was diminished upon beta-MCD treatment as revealed by chemical cross-linking. Mice with a genetic mutation in the Niemann-Pick C1 gene developing a defect in cholesterol sorting showed significantly reduced amounts of the synaptophysin/synaptobrevin complex compared to their homo- or heterozygous littermates. Finally when using primary cultures of mouse hippocampus the synaptophysin/synaptobrevin complex was down-regulated after depleting the endogenous cholesterol content by the HMG-CoA-reductase inhibitor lovastatin. Alternatively, treatment with cholesterol up-regulated the synaptophysin/synaptobrevin interaction in these cultures. These data indicate that the synaptophysin/synaptobrevin interaction critically depends on a high cholesterol content in the membrane of synaptic vesicles. Variations in the availability of cholesterol may promote or impair synaptic efficiency by interfering with this complex.
Mitter
Diana
D
Institut für Anatomie der Charité, Mathematisch-natur-wissenschaftliche Fakultät I, Humboldt Universität zu Berlin, Berlin, Germany.
Reisinger
Clemens
C
Hinz
Britta
B
Hollmann
Susanne
S
Yelamanchili
Sowmya V
SV
Treiber-Held
Stephanie
S
Ohm
Thomas G
TG
Herrmann
Andreas
A
Ahnert-Hilger
Gudrun
G
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D003505:Cyclodextrins / Q000494:pharmacology; D003902:Detergents; D005372:Filipin / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism; D017830:Octoxynol; D021381:Protein Transport; D050683:R-SNARE Proteins; D051381:Rats; D012995:Solubility; D013572:Synaptic Vesicles / Q000378:metabolism; D016708:Synaptophysin / Q000737:chemistry / Q000378:metabolism*; D015854:Up-Regulation
D000924:Anticholesteremic Agents; D003505:Cyclodextrins; D003902:Detergents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D050683:R-SNARE Proteins; D016708:Synaptophysin; D005372:Filipin; D017830:Octoxynol; D002784:Cholesterol; D008148:Lovastatin