Dev Cell

Membrane lipid regulation of cell function is poorly understood. In early development, sterol efflux and the ganglioside GM1 regulate sperm acrosome exocytosis (AE) and fertilization competence through unknown mechanisms. Here, we show that sterol efflux and focal enrichment of GM1 trigger Ca(2+) influx necessary for AE through CaV2.3, whose activity has been highly controversial in sperm. Sperm lacking CaV2.3's pore-forming \uce\ub11E subunit showed altered Ca(2+) responses, reduced AE, and a strong subfertility phenotype. Surprisingly, AE depended on spatiotemporal information encoded by flux through CaV2.3, not merely the presence/amplitude of Ca(2+) waves. Using studies in both sperm and voltage clamp of Xenopus oocytes, we define a molecular mechanism for GM1/CaV2.3 regulatory interaction, requiring GM1's lipid and sugar components and CaV2.3's \uce\ub11E and \uce\ub12\uce\ub4 subunits. Our results provide a mechanistic understanding of membrane lipid regulation of Ca(2+) flux and therefore Ca(2+)-dependent cellular and developmental processes such as exocytosis and fertilization.8DP1-EB016541/DP/NCCDPHP CDC HHS/United StatesDP-OD-006431/OD/NIH HHS/United StatesDP1 EB016541/EB/NIBIB NIH HHS/United StatesDP1 OD006431/OD/NIH HHS/United StatesR01 HD045664/HD/NICHD NIH HHS/United StatesR01-HD-045664/HD/NICHD NIH HHS/United States2015-02-10T00:00:00Z24525187PMC394708