Modulators of calcium signalling at fertilization

Abstract

Calcium (Ca 2+ ) signals initiate egg activation across the animal kingdom and in at least some plants. These signals are crucial for the success of development and, in the case of mammals, health of the offspring. The mechanisms associated with fertilization that trigger these signals and the molecules that regulate their characteristic patterns vary widely. With few exceptions, a major contributor to fertilization-induced elevation in cytoplasmic Ca 2+ is release from endoplasmic reticulum stores through the IP3 receptor. In some cases, Ca 2+ influx from the extracellular space and/or release from alternative intracellular stores contribute to the rise in cytoplasmic Ca 2+ . Following the Ca 2+ rise, the reuptake of Ca 2+ into intracellular stores or efflux of Ca 2+ out of the egg drive the return of cytoplasmic Ca 2+ back to baseline levels. The molecular mediators of these Ca 2+ fluxes in different organisms include Ca 2+ release channels, uptake channels, exchangers and pumps. The functions of these mediators are regulated by their particular activating mechanisms but also by alterations in their expression and spatial organization. We discuss here the molecular basis for modulation of Ca 2+ signalling at fertilization, highlighting differences across several animal phyla, and we mention key areas where questions remain.

Diagnosis and Treatment of Male Infertility-Related Fertilization Failure

“…Then, IP 3 molecules will bind to its receptor (IP 3 R) present on the endoplasmic reticulum (ER), which will lead to the release of Ca 2+ from the ER stores (Figure 1). The support of long-lasting intermittent Ca 2+ oscillations occurs due to a dual regulation of IP 3 R. Decreased intracellular Ca 2+ concentrations increase IP 3 R sensitivity, which results in Ca 2+ release from the ER, while elevated Ca 2+ concentrations inhibit IP 3 R channels and halt Ca 2+ delivery to the cytoplasm [56,57]. The Ca 2+ oscillations will activate various oocyte kinases that will evoke different downstream events necessary for fertilization in a time-dependent order [58].…”

“…Thus, calcium oscillations are the central landmark of fertilization and they have been reported in all mammalian species studied to date. However, the exact Ca 2+ pattern is species-specific, with differences being found in the amplitude, duration, and frequency of the Ca 2+ spikes [57,65]. The characteristic pattern of Ca 2+ oscillations following ICSI of in vivo matured metaphase II (MII) human oocytes consists of a series of sharp increases in Ca 2+ concentration followed by a return to baseline concentrations [66].…”

Superovulation Does Not Alter Calcium Oscillations Following Fertilization

“…What is unusual about mammalian eggs is that following the initial calcium rise, they go on to have a series of oscillations in cytoplasmic calcium levels that persist for several hours after fertilization. These calcium oscillations drive downstream events of egg activation including exocytosis of cortical granules, activation of calcium/calmodulin-dependent protein kinase II-gamma, resumption of the cell cycle, and pronucleus formation, all of which are essential for initiating proper embryo development ( Stein et al, 2020 ). Persistent calcium oscillations can be triggered in the absence of sperm using the divalent cation strontium, resulting in parthenogenetic egg activation mediated by the transient receptor potential channel TRPV3 ( Fraser, 1987 ; Carvacho et al, 2013 ).…”

Superovulation does not alter calcium oscillations following fertilization

“…What is unusual about mammals is that following the initial calcium rise, they go on to have a series of oscillations in cytoplasmic calcium levels that persist for several hours after fertilization. These calcium oscillations drive downstream events of egg activation including exocytosis of cortical granules, activation of calcium/calmodulin-dependent protein kinase II-gamma, resumption of the cell cycle, and pronucleus formation, all of which are essential for initiating proper embryo development (Stein et al, 2020). In the mouse, an inappropriate pattern of calcium oscillations following fertilization is associated with reductions in implantation efficiency, reduced development to term, and abnormalities in offspring growth (Ozil and Huneau, 2001;Ducibella et al, 2002;Ozil et al, 2005Ozil et al, , 2006.…”

“…The pattern of calcium oscillations at fertilization is modulated by the amount of PLCζ released by the sperm but also by many factors intrinsic to the fertilized egg (Stein et al, 2020). Calcium oscillations depend on the amount of calcium in endoplasmic reticulum (ER) stores as well as egg factors that regulate how quickly calcium is released from the ER, cleared from the cytoplasm, and then pumped back into the ER such that sufficient calcium stores are available for the next calcium release event.…”