Mammalian fertilization comprises sperm migration through the female reproductive tract, biochemical and morphological changes to sperm, and sperm-egg interaction in the oviduct. Although the broad concepts of fertilization are well defined, our understanding of the biochemical mechanisms underlying sperm-egg binding is limited.
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Lishko PV, Botchkina IL, Kirichok Y.; ''Progesterone activates the principal Ca2+ channel of human sperm.''; PubMedEurope PMCScholia
Smith JF, Syritsyna O, Fellous M, Serres C, Mannowetz N, Kirichok Y, Lishko PV.; ''Disruption of the principal, progesterone-activated sperm Ca2+ channel in a CatSper2-deficient infertile patient.''; PubMedEurope PMCScholia
Tranter R, Read JA, Jones R, Brady RL.; ''Effector sites in the three-dimensional structure of mammalian sperm beta-acrosin.''; PubMedEurope PMCScholia
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Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E.; ''Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity.''; PubMedEurope PMCScholia
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Ikawa M, Inoue N, Benham AM, Okabe M.; ''Fertilization: a sperm's journey to and interaction with the oocyte.''; PubMedEurope PMCScholia
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CatSper (CATionic channel of SPERm), a pH regulated, principal flagellar calcium ion channel. CatSper is a core regulator of sperm tail calcium entry and sperm motility. All CatSper subunits are sperm specific proteins and are located in the principal piece of the sperm flagellum. The sperm specific CatSper channel controls the intracellular Ca(2+) concentration. Progesterone activates human CatSper, but not mouse, at low nanomolar concentrations by shifting the voltage dependency of the human CatSper channel into the physiological range. The pore of the CatSper channel is formed by four different CATSPER proteins (CATSPER 1, 2, 3, and -4) and all four are required for formation of the functional channel. In addition, three auxiliary subunits (CATSPERB, CATSPERG and CATSPERD) make this complex to be the one of the most sophisticated mammalian ion channels known. Only CATSPER1 is believed to be regulated by pH. The absence of any of the pore-forming CATSPER proteins, or gamma or beta auxiliary subunits- leads to disappearance of the whole CatSper channel. Syndromic male infertility (SMI) in association with CATSPER mutations is described in a number of human gene mutation studies. The absence of CatSper channel leads to male infertility both in mice and humans.
In humans induction of acrosome reaction is mediated by ADAM and B4GALT1 binding to ZP3 and ZP4. Binding of ZP3 to its putative sperm receptor zona receptor kinase, leads to its aggregation and downstream cAMP signaling.
Intracellular alkalinization is essential for the initiation of motility, capacitation, hyperactivation, and the acrosome reaction. Hv1 mediates the voltage-dependent proton permeability of excitable membranes. Hv1 is abundantly expressed in human sperm cells within the principal piece of the sperm flagellum, making it ideally positioned to activate pH-dependent proteins of the axoneme and thus to control sperm motility.
Acrosin is localized in the acrosomal matrix as an enzymatically inactive zymogen, proacrosin. Upon stimulation by zona pellucida binding and ca2+ influx, proacrosin is cleaved into a heavy and light chain.
The mebrane of the post-acrosomal reaction sperm and the membrane of the oocyte are bound to one another by the CD9 transmembrane protein on the oocyte and the Izumo transmembrane protein on the sperm.
Slo3 represents a new and unique type of potassium channel regulated by intracellular pH. Slo3 is sperm specific and controls membrane potential. Incapacitated murine spermatozoa hyperpolarize to approximately 60 mV during capacitation, an effect attributed to an increase in K+ permeability. KSper (potassium transport in sperm) is the dominant, if not the only, K+ selective channel in mouse epididymal spermatozoa.
Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg's protective vestments. Progesterone induces Ca2+ influx into spermatozoa and triggers multiple Ca2+-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg. Progesterone dramatically potentiates CatSper calcium transport activity, identifying CatSper as the progesterone receptor of sperm.
The fertilizing spermatozoon must penetrate the surrounding cumulus mass, (or cumulus oophorus), consisting of follicular cells dispersed in a polymerized matrix composed mainly of hyaluronic acid.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1187000
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