title: Lipid modulation of calcium flux through CaV2.3 regulates acrosome exocytosis and fertilization.
abstract: 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.
authors: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hungerford Hill Road, Ithaca, NY 14853, USA.
authors: Roy
authors: R
authors: Cohen
authors: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hungerford Hill Road, Ithaca, NY 14853, USA.
authors: Danielle E
authors: DE
authors: Buttke
authors: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hungerford Hill Road, Ithaca, NY 14853, USA.
authors: Atsushi
authors: A
authors: Asano
authors: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hungerford Hill Road, Ithaca, NY 14853, USA.
authors: Chinatsu
authors: C
authors: Mukai
authors: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hungerford Hill Road, Ithaca, NY 14853, USA.
authors: Jacquelyn L
authors: JL
authors: Nelson
authors: Department of Biochemistry and Molecular Pharmacology, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
authors: Dongjun
authors: D
authors: Ren
authors: Department of Biochemistry and Molecular Pharmacology, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
authors: Richard J
authors: RJ
authors: Miller
authors: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors: Moshe
authors: M
authors: Cohen-Kutner
authors: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors: Daphne
authors: D
authors: Atlas
authors: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hungerford Hill Road, Ithaca, NY 14853, USA. Electronic address: ajt32@cornell.edu.
authors: Alexander J
authors: AJ
authors: Travis
mesh_terms: D000177:Acrosome / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020908:Calcium Channels, R-Type / Q000502:physiology*; D027682:Cation Transport Proteins / Q000502:physiology*; D002478:Cells, Cultured; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D005306:Fertilization / Q000187:drug effects / Q000502:physiology*; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism*; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism
chemical_list: C423009:CACNA1E protein, human; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D005677:G(M1) Ganglioside; D002118:Calcium