TY - JOUR
T1 - Lipid Modulation of Calcium Flux through CaV2.3 Regulates Acrosome Exocytosis and Fertilization
AU - Cohen, Roy
AU - Buttke, Danielle E.
AU - Asano, Atsushi
AU - Mukai, Chinatsu
AU - Nelson, Jacquelyn L.
AU - Ren, Dongjun
AU - Miller, Richard J.
AU - Cohen-Kutner, Moshe
AU - Atlas, Daphne
AU - Travis, Alexander J.
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01-HD-045664 and 8DP1-EB016541 (formerly DP-OD-006431; A.J.T.), the Cornell College of Veterinary Medicine Dual DVM/PhD Degree Program (D.E.B.), the Cornell Center for Vertebrate Genomics (A.J.T.), and the Baker Institute for Animal Health. A.J.T. is founder and an officer of Androvia, Inc., which has interest in diagnostic assays for male fertility based on sperm function.
PY - 2014/2/10
Y1 - 2014/2/10
N2 - 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ flux and therefore Ca2+-dependent cellular and developmental processes such as exocytosis and fertilization.
AB - 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ flux and therefore Ca2+-dependent cellular and developmental processes such as exocytosis and fertilization.
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U2 - 10.1016/j.devcel.2014.01.005
DO - 10.1016/j.devcel.2014.01.005
M3 - Article
C2 - 24525187
AN - SCOPUS:84893581116
SN - 1534-5807
VL - 28
SP - 310
EP - 321
JO - Developmental Cell
JF - Developmental Cell
IS - 3
ER -