The receptors for the second messenger inositol 1,4,5-trisphosphate (IP3) constitute a family of Ca2+ channels responsible for the mobilization of intracellular Ca2+ stores. The inositol 1,4,5-trisphosphate receptor (IP3R) is an intracellular Ca2+ release channel responsible for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned, and their genes have been classified into a family (Patel et a., 1999).
IP3Rs are tetramers that act as ligand-gated channels facilitating Ca2+ release from internal stores/endoplasmic reticulum.
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Oogenesis, Oocyte maturation
Comment
Reorganization of the Endoplasmic Reticulum and Development of Ca2+ Release Mechanisms During Meiotic Maturation of Human Oocytes. Mann JS et al. Oocyte maturation in rodents is characterized by a dramatic reorganization of the endoplasmic reticulum (ER) and an increase in the ability of an oocyte to release Ca(2+) in response to fertilization or inositol 1,4,5-trisphosphate (IP(3)). We examined if human oocytes undergo similar changes during cytoplasmic meiotic maturation both in vivo and in vitro. Immature, germinal vesicle (GV)-stage oocytes had a fine network of ER throughout the cortex and interior, whereas the ER in in vivo-matured metaphase II (MII)-stage oocytes was organized in large (~2-3 microm) accumulations throughout the cortex and interior. Likewise, oocytes matured in vitro exhibited cortical and interior clusters with no apparent polarity with regard to the meiotic spindle. In vivo-matured oocytes contained approximately 1.5X the amount of IP3 receptor protein and released significantly more Ca(2+) in response to IP(3) than GV-stage oocytes; however, oocytes matured in vitro did not contain more IP(3) receptor protein or release more Ca(2+) in response to IP(3) than GV-stage oocytes. These results show that at least one cytoplasmic change occurs during in vitro maturation of human oocytes that might be important for fertilization and subsequent embryonic development but suggest that a low developmental competence of in vitro matured oocytes could be due to deficiencies in the ability to release Ca(2+) at fertilization.
During maturation, mammalian oocytes undergo a series of changes that prepare them for fertilization. These events are regulated by kinases, most notably histone H1 and mitogen-activated protein kinase. Intracellular calcium ([Ca2+]i) oscillations participate in oocyte signaling, and it has been postulated that they play a role in oocyte maturation. Mammalian fertilization is characterized by the presence of long-lasting intracellular calcium oscillations that are required to induce oocyte activation. One of the Ca2+ channels that may mediate this Ca2+ release is the inositol 1,4,5-trisphosphate receptor (IP3R). Three isoforms of the receptor have been described, but their expression in oocytes and possible roles in mammalian fertilization are not well known. Initiation of development in fertilized mammalian metaphase II (MII) oocytes requires the presence of long-lasting intracellular calcium ([;t1Ca2+]i) oscillations. These oscillations are responsible for promoting reinitiation and completion of meiosis, release of cortical granules, pronuclear formation, and first mitotic cleavage. The signaling mechanism by which the sperm triggers and maintains this periodical Ca2+ release in oocytes is not fully elucidated, although inositol 1,4,5-trisphosphate (IP3), a widespread Ca2+-releasing molecule produced from the hydrolysis of phosphatidylinositol 4,5-bisphosphate catalyzed by phospholipase C, and its receptor (IP3R), are likely to be involved.
Expression regulated by
Comment
He et al. (1997 and 1999) reported that 1) the three IP3R isoforms are expressed in bovine oocytes; 2) IP3R-1 is likely to mediate most of the Ca2+ release during fertilization; 3) its down-regulation may explain the decline in amplitude of sperm-induced [Ca2+]i rises as fertilization progresses toward pronuclear formation; and 4) agonists of the IP3R induce down-regulation of the type-1 receptor in oocytes similar to that evoked by fertilization.
Ovarian localization
Oocyte, Granulosa
Comment
Follicle stages
Primary, Secondary, Antral, Preovulatory
Comment
Using specific antibodies to the type 1, 2, and 3 IP3R Fissore et al. (1999) tested the hypotheses that different IP3R isoforms are responsible for the internal Ca2+ elevation and that they contribute to the maturation-associated acquisition of IP3 sensitivity. In both preovulatory oocytes and ovulated eggs of CF-1 mice, immunofluorescence revealed that types 1 and 2 isoforms were present in the cell cortex and interior. Type 1 was observed throughout the cytoplasm, and Western analysis indicated a 1.9-fold maturation-associated increase. In contrast, the signals detected for the type 2 (high-affinity) isoform and type 3 were present to a lesser extent, with type 2 restricted to isolated islands (similar to aggregates of vesicles detected by electron microscopy), which, in the cortex, may amplify early sperm-egg signaling events. Types 1 and 2 isoforms were also present in granulosa cells. Fujino et al. (1995) also reported that IP3R2 mRNA was localized in the follicular granulosa cells of the ovary. Using polyclonal antibodies raised against purified IP3 receptors through immunoblotting and immunohistochemistry, Nakanishi et al. (1996) also reported that IP3 receptor staining was intense in the cytoplasm of oocytes in the primary follicle, but then attenuated as these cells matured.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Matsumoto et al. (1999) have obtained mice with disruption of this IP3R1 gene, in which brain IP3-induced calcium release was almost completely abolished. They were rarely born alive, indicating that IP3R1 has some functions during embryonic development. Animals exhibited severe neurological symptoms, ataxia and epilepsy, and were shown to be deficient in the cerebellar long-term depression.