TRPM7 and Ca_V3.2 channels mediate Ca²⁺ influx required for egg activation at fertilization.

Abstract

The success of mammalian development following fertilization depends on a series of transient increases in egg cytoplasmic Ca²⁺, referred to as Ca²⁺ oscillations. Maintenance of these oscillations requires Ca²⁺ influx across the plasma membrane, which is mediated in part by T-type, Ca_V3.2 channels. Here we show using genetic mouse models that TRPM7 channels are required to support this Ca²⁺ influx. Eggs lacking both TRPM7 and Ca_V3.2 stop oscillating prematurely, indicating that together they are responsible for the majority of Ca²⁺ influx immediately following fertilization. Fertilized eggs lacking both channels also frequently display delayed resumption of Ca²⁺ oscillations, which appears to require sperm-egg fusion. TRPM7 and Ca_V3.2 channels almost completely account for Ca²⁺ influx observed following store depletion, a process previously attributed to canonical store-operated Ca²⁺ entry mediated by STIM/ORAI interactions. TRPM7 serves as a membrane sensor of extracellular Mg²⁺ and Ca²⁺ concentrations and mediates the effects of these ions on Ca²⁺ oscillation frequency. When bred to wild-type males, female mice carrying eggs lacking TRPM7 and Ca_V3.2 are subfertile, and their offspring have increased variance in postnatal weight. These in vivo findings confirm previous observations linking in vitro experimental alterations in Ca²⁺ oscillatory patterns with developmental potential and offspring growth. The identification of TRPM7 and Ca_V3.2 as key mediators of Ca²⁺ influx following fertilization provides a mechanistic basis for the rational design of culture media that optimize developmental potential in research animals, domestic animals, and humans.