Lipid modulation of calcium flux through CaV2.3 regulates acrosome exocytosis and fertilization.
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 α1E 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 α1E and α2δ 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.
PubMed ID: 24525187
PMC ID: PMC3947087
Article link: Dev Cell.
Grant support: DP1 EB016541 NIBIB NIH HHS , DP1 OD006431 NIH HHS , R01 HD045664 NICHD NIH HHS , 8DP1-EB016541 NCCDPHP CDC HHS, DP-OD-006431 NIH HHS , R01-HD-045664 NICHD NIH HHS , P30 CA060553 NCI NIH HHS
Genes referenced: cacna1e cav2