Human Reproduction Update Advance Access originally published online on July 24, 2008
Human Reproduction Update 2008 14(6):647-657; doi:10.1093/humupd/dmn029
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Control of hyperactivation in sperm
Department of Biomedical Sciences, T5-002B Veterinary Research Tower, Cornell University Ithaca, NY 14853, USA
1 Correspondence address. Tel: +1-607-253-3589; Fax: +1-607-253-3541; E-mail: sss7{at}cornell.edu
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Abstract |
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Abstract
Hyperactivation is required for...BACKGROUND: Sperm hyperactivation is critical to fertilization, because it is required for penetration of the zona pellucida. Hyperactivation may also facilitate release of sperm from the oviductal storage reservoir and may propel sperm through mucus in the oviductal lumen and the matrix of the cumulus oophorus. Hyperactivation is characterized by high amplitude, asymmetrical flagellar bending.
METHODS: This is a review of the original literature on the mechanisms that regulate hyperactivation, including physiological factors and signaling pathways.
RESULTS: Computer-assisted semen analysis systems can be used to identify hyperactivated sperm by setting minimum thresholds for curvilinear velocity (VSL) and lateral head movement and a maximum threshold for path linearity. Hyperactivation is triggered by a rise in flagellar Ca2+ resulting from influx primarily through plasma membrane CatSper channels and possibly also by release of Ca2+ from a store in the redundant nuclear envelope. It requires increased pH and ATP production. The physiological signals that trigger the rise in Ca2+ remain elusive, but there is evidence that the increased Ca2+ acts through a calmodulin/calmodulin kinase pathway. Hyperactivation is considered part of the capacitation process; however, the regulatory pathway that triggers hyperactivation can operate independently from that which prepares sperm to undergo the acrosome reaction. Hyperactivation may be modulated by chemotactic signals to turn sperm toward the oocyte.
CONCLUSIONS: Little is known about exactly what triggers hyperactivation in human sperm. This information could enable clinicians to develop reliable fertility assays to assess normal hyperactivation in human sperm samples.
Key words: sperm hyperactivation / intracellular calcium / CatSper / signaling pathways / human sperm
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Hyperactivation is required for fertility |
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In 1970, Yanagimachi reported that hamster sperm became extremely active as they gained the ability to fertilize oocytes in vitro. He observed that sperm swimming in this manner could be seen through the walls of the oviductal ampulla and proposed that this ‘hyper-active’ movement provides sperm with greater propulsion for reaching the oocyte or for passing through the cumulus and zona pellucida (Yanagimachi, 1970
).
Years later, Yanagimachi's proposals were confirmed by various observations and experiments. Upon entering the oviduct, sperm encounter a mucous secretion that is quite thick in some species (Jansen, 1978; Jansen, 1980; Jansen and Bajpai, 1982; Suarez et al., 1997). In the human oviduct, thick mucus secretions were found in isthmic segments taken from women in the late follicular phase (Jansen, 1980). In vitro, boar sperm that were not hyperactivated were observed to stick to pig oviductal mucus and fail to penetrate it (Suarez et al., 1992). Mucus increases the viscosity and elasticity of the aqueous milieu in which sperm swim. When mouse and hamster sperm are placed in medium made highly viscoelastic by addition of methyl cellulose or long-chain polyacrylamide, sperm that are hyperactivated move through it more effectively than those that are not (Suarez et al., 1991; Suarez and Dai, 1992). Sperm from CatSper null mutant mice, which are unable to hyperactivate, do not penetrate artificial mucus as well as hyperactivating wild-type sperm (Quill et al., 2003). Thus, hyperactivated sperm are likely to be more effective at swimming through oviductal mucus in vivo.
In addition to viscoelastic mucus secreted into the oviduct, sperm also encounter a highly viscoelastic environment when they enter the matrix of the oocyte's cumulus oophorus. The high viscoelasticity of the cumulus matrix is primarily attributed to hyaluronan (Dandekar et al., 1992). Although penetration of the matrix may be assisted by hyaluronidase expressed on the surface of the sperm head (Kim et al., 2005), hyperactivation would undoubtedly assist sperm as well.
There is strong evidence that hyperactivation is required for penetrating the zona pellucida. Hamster sperm were incubated under capacitating conditions until they hyperactivated and then were added to oocytes. After the sperm bound to the zonae, Ca2+ channel blockers were added to inhibit hyperactivation. Although the sperm remained motile and underwent acrosome reactions, most failed to penetrate the zonae (Stauss et al., 1995). Years after those experiments, mice that were null mutants for CatSper proteins were developed. The sperm from the nulls were progressively motile and could undergo acrosome reactions; however, they could not hyperactivate and failed to penetrate the zonae pellucidae of oocytes in vitro. If the zonae were removed, the sperm were able to fertilize normally (Ren et al., 2001; Quill et al., 2003).
The behavior of hamster and mouse sperm swimming within transilluminated oviducts suggested to observers that hyperactivation also enables sperm to move about effectively in the oviductal lumen. While hyperactivated sperm placed on a microscope slide in simple aqueous medium often spend much of their time swimming in circles, those observed swimming within the oviduct cover space rapidly in a manner that should increase chances of encountering the cumulus–oocyte complex. This is at least partly because the surfaces sperm encounter in the oviduct are not hard and flat like those of microscope slides. Hyperactivated hamster sperm were seen to glide rapidly over the mucosal surface of the ampulla (Katz and Yanagimachi, 1980). Mouse sperm were observed to use the deep flagellar bends characteristic of hyperactivation to turn around within pockets of mucosa and escape out into the central lumen (Suarez and Osman, 1987). It has not been possible to observe the behavior of sperm within the oviducts of humans; however, it is known that they encounter a similar environment, consisting of a highly folded mucosa and complex narrow passageways.
In many mammalian species, a reservoir of sperm forms within the isthmus of the oviduct when sperm become attached to the mucosal epithelium (reviewed by Suarez and Pacey, 2006). There is evidence that the attachment of sperm to epithelium prolongs their motile lives (Pollard et al., 1991; Gwathmey et al., 2006). In several species, this interaction is known to involve carbohydrate recognition; that is, protein on the surface of sperm binds specifically to a glycosylated receptor on the epithelium (Suarez and Pacey, 2006). In cattle, the proteins on sperm that bind them to the epithelium have been identified as members of the BSP (bovine seminal plasma) family (Gwathmey et al., 2003, 2006). The oviductal receptors for the BSP proteins contain fucose and have been identified as members of the annexin family of proteins (Ignotz et al., 2007). As bull sperm become capacitated, they shed at least one of the BSP proteins (Gwathmey et al., 2003). In the oviduct, capacitation would thus reduce binding affinity of sperm for the oviductal epithelium. As sperm lose binding affinity for epithelial receptors, hyperactivation could assist them in pulling off of the epithelium. In the mouse, only sperm exhibiting hyperactivated movement in the oviduct were observed to detach from the epithelium (DeMott and Suarez, 1992).
Human sperm observed detaching from oviductal epithelium in vitro showed a greater incidence of hyperactivation than sperm that had not yet attached to epithelium (Pacey et al., 1995), which indicates that hyperactivation may be required to pull human sperm from the epithelium and/or that binding to the epithelium hyperactivates human sperm.
Altogether, the evidence indicates that all of Yanagimachi's proposals were correct. After sperm enter the oviduct, hyperactivation enables them to reach oocytes and penetrate their vestments. Whereas hyperactivation may serve all of these functions in human sperm, this should be verified by direct investigation. Hyperactivation likely assists human sperm in penetrating viscoelastic materials, because human sperm do encounter mucus in the oviduct (Jansen, 1980), and must also penetrate a viscoelastic cumulus matrix and the zona pellucida. However, hyperactivation has not been observed directly within the human oviduct and detailed reports on the swimming patterns of sperm recovered from the human oviduct are lacking.
The objective of this review was to synthesize published findings on the mechanisms that regulate hyperactivation, including physiological factors and signaling pathways that trigger hyperactivation in motile sperm. Sperm develop the ability to swim as they pass through the epididymis and rapidly begin to swim (activate) as they are released from the epididymis. For reviews on maturation of the motile apparatus and activation of motility, please see Eddy (2006) or Turner (2003, 2006).
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The flagella of hyperactivated sperm beat asymmetrically |
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In most species, mature sperm are held immotile within the epididymis until they are released, whereupon they quickly begin to swim. This process is known as activation of motility. Activated sperm generate nearly symmetrical flagellar beats (Fig. 1), which propel them in nearly linear trajectories (Suarez and Dai, 1992
; Mortimer and Swan, 1995a; Ho et al., 2002). When sperm become hyperactivated, the amplitude of the flagellar bend increases, usually only on one side of the flagellum. This produces a beat pattern that is highly asymmetrical, often causing hyperactivated sperm to swim in circles on glass slides. Extremely asymmetrical bends produce figure-of-eight movement patterns. During asymmetrical flagellar beating, steady rolling of the head can result in helical tracks, which have been described for hyperactivated human sperm (Morales et al., 1988). In some species, particularly mice, hyperactivated sperm trace erratic paths due to intermittent production of deep bends. One could argue that this represents switching back and forth between the activated and hyperactivated state, but only instantaneous assessment of signaling, which has not been done, can address the issue.
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CASA can assess hyperactivation, although imperfectly |
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Computer-assisted semen analysis (CASA) has been used to detect hyperactivation and to identify the percentage of sperm in a sample that are hyperactivated. An accepted procedure for defining hyperactivation by a particular CASA system is to incubate sperm under conditions that support in vitro fertilization (that is, ‘capacitating’ conditions) and compare swimming patterns of those sperm with control sperm that have been incubated an equal amount of time under noncapacitating conditions. The investigator then identifies measurements that are affected by the capacitating conditions and uses the information to set threshold values for identifying hyperactivated sperm (Mortimer and Mortimer, 1990
; Murad et al., 1992; Mortimer, 1997; Kay and Robertson, 1998). This has been the approach used to identify hyperactivation in human sperm, because of the difficulties involved in observing sperm in the Fallopian tubes of women or recovering tubal sperm. Incubation under capacitating conditions, however, does not work for some species, such as bull sperm, which do not show significant changes in movement patterns when incubated in capacitation medium (Marquez and Suarez, 2004).
To have the CASA system identify hyperactivated sperm, thresholds are usually set for a minimum curvilinear velocity and a maximum path linearity (that is, a minimum curvature of path trajectory). In addition, a minimum threshold is often set for the distance that the sperm head moves side-to-side as the sperm advances, which is known as the amplitude of lateral head displacement (ALH). This is an indirect measure of flagellar bend amplitude, because the head is wagged from side-to-side by the developing principal and reverse bends and it gets wagged farther from side-to-side by deeper flagellar bends. Because ALH is not a direct measurement of the flagellar bend, it is imperfect; however, CASA systems compensate considerably for the lack of accuracy with reasonable precision and acquisition of data from hundreds of sperm in less than a minute. CASA systems can miss hyperactivated sperm that swim in very tight circles, because they cannot track them properly. Image or frame collection rate can also affect the accuracy of the system (Mortimer and Swan, 1995a; Mortimer, 1997). Playback features should always be used to check the accuracy of the system and re-adjust thresholds if necessary. For human sperm, threshold values have been established for some CASA systems; however, there are no universally accepted criteria. For more detailed discussions of the use of CASA systems to measure hyperactivation, see (Mortimer, 1997; Kay and Robertson, 1998).
Because most CASA systems can only track and analyze head movements, investigators who study the regulation of flagellar movement use other methods to characterize the flagellar wave. In most mammalian sperm, irregular flagellar waveforms do not allow one to bisect waves in order to get accurate measures of amplitude and wavelength. Instead, other methods are used to assess waves. The most common is to measure curvature at points along the flagellum and to then plot curvature against distance from the base of the flagellum (Carlson et al., 2005; Ishijima et al., 2006). However, even with assistance from image analysis software, this process is extremely tedious and time-consuming. First, digital videos of the moving sperm must be obtained and then individual frames must be selected for analysis of the flagellar bends. It is only practical to make these measures of curvature on 10–20 sperm per treatment sample. Such low sample numbers can only provide representative measures of the population if the sperm behave fairly uniformly or if a uniform subgroup is identified for sampling. To say the least, it is difficult to make this type of analysis of human semen samples, which are notoriously heterogeneous.
CASA and curvature values are affected by viscosity of the medium, because high viscosity dampens flagellar waves. Also, sticking of sperm heads to surfaces in the slide chamber affect curvature. Acrosome-reacted sperm are especially sticky. Due to the large size of the acrosome in hamster sperm, acrosomal status cannot be ascertained on hyperactivated sperm without special staining (Suarez and Dai, 1995). The reacted sperm can be seen to stick to glass, even in the presence of albumin, and sticking results in an increase in the amplitude of the reverse bend, which often switches the bending pattern from asymmetrical to symmetrical (Suarez, personal observations). Sticking can be minimized by coating surfaces with nonstick agents such as agar (Suarez et al., 1991) or agarose (Ignotz and Suarez, 2005).
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Ca2+ signaling triggers hyperactivation |
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Ca2+ is the primary second messenger that triggers hyperactivated motility. Treating sperm with Ca2+ ionophores A23187 [GenBank] or ionomycin induces hyperactivation (Suarez et al., 1987
, 1992; Marquez and Suarez, 2006; Xia et al., 2007). Using the fluorescent Ca2+ indicator indo-1, cytoplasmic Ca2+ levels were measured in the flagella of hyperactivated hamster sperm and found to be higher than in activated sperm (Suarez et al., 1993). Other fluorescent Ca2+ indicators have also detected intracellular Ca2+ increases during stimulation of hyperactivation (Ho and Suarez, 2001; Xia et al., 2007).
Demembranated sperm models have been used to study the regulation of hyperactivated motility. Sperm are demembranated by treatment with Triton X-100 to disrupt the plasma membrane, mitochondrial membranes and acrosomal membranes—leaving intact the nucleus, cytoskeletal elements and proteins anchored to these structures. In the flagellum, the intact cytoskeleton includes the axoneme, dense outer fibers and fibrous sheath (Ho et al., 2002). After demembranation, sperm are immotile; however, they can be reactivated by transfer to an ‘intracellular medium’ (low in Na+ and high in K+) and adding ATP. Demembranated bull sperm reactivate in intracellular medium containing 
50 nM of Ca2+. When the Ca2+ is raised to 100 nM, some sperm begin to hyperactivate, and most hyperactivate when Ca2+ reaches 400 nM (Ho et al., 2002). The responses of demembranated sperm indicate that Ca2+ acts directly upon cytoskeletal elements to regulate motility, because membranes and soluble cytoplasmic elements are gone. Similar results are obtained with demembranated/reactivated sea urchin sperm, which lack dense outer fibers and the fibrous sheath (Brokaw and Nagayama, 1985), indicating that the Ca2+ affects the axoneme directly, rather than through the other skeletal structures. Selective regulation of the activity of a group of dynein arms by Ca2+ was demonstrated to be the basis for the changes in flagellar bending patterns brought about by high Ca2+ concentrations in demembranated sea urchin sperm (Bannai et al., 2000).
Demembranation studies have not been conducted on human sperm to study Ca2+ regulation of hyperactivation, although human sperm have been successfully reactivated after demembranation (Murad et al., 1992). Sperm from cynomolgus monkeys have been demembranated and reactivated; they show similar responses to raised Ca2+ in the reactivation medium as those reported for bull sperm (Ishijima et al., 2006).
Demembranated sperm have been used further to identify the target of the Ca2+ signal. When calmodulin (CaM) was extracted from bull sperm during demembranation, motility was not reactivated unless exogenous CaM was added back. Adding 1 µm Ca2+ with CaM hyperactivated the reactivated demembranated sperm. When peptide inhibitors of calmodulin kinase II (CaMKII) were added with the CaM, hyperactivation was reduced by 75%; whereas, W-7 or a peptide inhibitor of myosin light chain kinase added with the CaM did not inhibit hyperactivation. Furthermore, when intact motile sperm were treated with KN-93, a membrane-permeant inhibitor of CaMKII, caffeine-induced hyperactivation was inhibited without impairing normal motility. The inactive analog KN-92 had no effect (Ignotz and Suarez, 2005). CaM and CaMKII were immunolocalized to the flagellum in bull and mouse sperm (Ignotz and Suarez 2005; Schlingmann et al., 2007). Altogether, these results indicate that hyperactivation is triggered by Ca2+/CaM activation of CaMKII.
In human sperm, motility declined over time in the presence of CaM kinase inhibitors KN-93 and KN-62, but no specific inhibition of hyperactivation was observed. The inhibitors caused a reduction in ATP content, which could account for the decreased motility. CaMKIV was detected in the flagellum using a monoclonal antibody, but a monoclonal antibody against CaMKII did not detect its presence (Marin-Briggiler et al., 2005). Thus, additional investigations are needed regarding the role of CaM kinases in regulation of human sperm motility and hyperactivation.
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Plasma membrane channels and intracellular stores can provide Ca2+ for hyperactivation |
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Second messenger Ca2+ can come from two sources: extracellular Ca2+ brought in through plasma membrane channels and/or Ca2+ stored in organelles (Fig. 2). The predominant source of Ca2+ for hyperactivation is extracellular Ca2+ brought in through plasma membrane Ca2+ channels formed by proteins in the CatSper family (Kirichok et al., 2006
). CatSper proteins are only expressed in male germ cells and localize to the principal piece of the flagellum in mature sperm (Carlson et al., 2005; Jin et al., 2007). The channels can be activated by raising intracellular pH (Kirichok et al., 2006). Male mice that are null mutants for CatSper-1, -2, -3 or -4 are infertile and the infertility has been correlated to a failure to hyperactivate (Ren et al., 2001; Quill et al., 2003; Jin et al., 2007; Qi et al., 2007). As described above, CatSper null sperm fail to penetrate the zona pellucida, but can fertilize oocytes from which the zona has been removed (Ren et al., 2001; Quill et al., 2003). While CatSper null sperm can swim progressively, the pattern of flagellar bending in the activated sperm is actually slightly abnormal and resembles that of wild-type sperm treated with a cell-permeant form of the Ca2+ chelator BAPTA to lower intracellular Ca2+ (Marquez et al., 2006). This indicates that the sperm cannot maintain even the low Ca2+ levels required to support normal activated motility and this deficit could also contribute to infertility.
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Homologs to murine CatSper genes have been identified in the human genome. Transcripts of CatSper genes were detected in higher amounts in human semen samples with high sperm motility than those with low sperm motility (Li et al., 2007
); however, the functional significance of mRNA in samples of mature sperm is unclear. Three brothers who were homozygous for a mutation followed by a deletion on chromosome 15 that encompassed the last two exons of CatSper2 were infertile. Sperm numbers were normal, but sperm motility and morphology were abnormal, with >90% of sperm showing short, coiled flagella (Avidan et al., 2003). In a limited study, the group mean expression of CatSper was lower in subfertile patients whose sperm showed motility deficits than in subfertile patients whose sperm showed normal motility (Nikpoor et al., 2004).
Other types of plasma membrane Ca2+ channels have been detected in mammalian sperm. Various voltage-gated Ca2+ channels have been detected in mouse and human sperm (Wennemuth et al., 2000; Trevino et al., 2004; Carlson et al., 2005). Transient receptor potential (TRPC-1, -3, -4, -6) channels (Castellano et al., 2003) have been identified in the principal pieces of human sperm flagella by antibody labeling. Cyclic nucleotide-gated Ca2+ channels have been localized to bull sperm flagella (Wiesner et al., 1998).
Null mutant mice have been developed for some of these voltage-gated channels (Platzer et al., 2000; Saegusa et al., 2000; Ino et al., 2001), TRPC4 channels (Freichel et al., 2001) and cyclic nucleotide-gated channel protein CNGA3 (Biel et al., 1999), but the null mutant males were not infertile. Nevertheless, homozygous null pups were underrepresented in heterozygotes crossings of voltage-gated Cav1.3 null mutants (Platzer et al., 2000) and Cav2.3 null mutant sperm showed greater straight-line velocity (VSL) and linearity (LIN) by CASA measurements in some media, indicating a reduction in the development of hyperactivation (Sakata et al., 2002). Null mutants of some types of Ca2+ channels were embryonic lethals (Seisenberger et al., 2000) or died shortly after birth (Jun et al., 1999) and thus could not be tested for effects on fertility. Furthermore, null mutants have not been produced against all members of these families of channels that might be present in sperm. Finally, although there is electrophysiological evidence that CatSper proteins are the only source of Ca2+ current in the flagella of mature sperm (Kirichok et al., 2006), other types of Ca2+ channels may have been present during the electrophysiological testing but inactived, e.g. by phosphorylation. Thus, other types of channels could contribute Ca2+ for hyperactivation without being absolutely essential to the process. For reviews of Ca2+ and other ion channels found in sperm, see (Darszon et al., 2006, 2007; Benoff et al., 2007; Publicover et al., 2007).
In addition to extracellular sources, Ca2+ for hyperactivation may be provided from a storage organelle in the base of the flagellum. Pharmacological agents known to release Ca2+ from stores induce hyperactivation in bull sperm, even in the absence of available extracellular Ca2+ (Ho and Suarez, 2001). Receptors for inositol 1,4,5-trisphosphate (IP3), which gate channels that release Ca2+ from intracellular stores, and calreticulin, the Ca2+ binding protein of reticular stores, were localized by antibodies to the base of the flagellum within a portion of the redundant nuclear envelope (RNE) (Ho and Suarez, 2001, 2003). The RNE is a cluster of membrane vesicles that originates from the nuclear envelope during condensation of the nucleus during spermiogenesis (Franklin, 1968; Toshimori et al., 1985). Unlike other excess organelles, the RNE is not discarded in the residual cytoplasm or cytoplasmic droplets and this is probably because it is not truly redundant but rather serves as an important Ca2+ store.
There is evidence for a functional RNE Ca2+ store in human sperm that responds pharmacologically as a ryanodine receptor-gated store, rather than as an IP3 receptor-gated store (Harper et al., 2004; Harper and Publicover, 2005).
The acrosome has also been identified as a functional Ca2+ store in mammalian sperm (Walensky and Snyder, 1995; O'Toole et al., 2000; Herrick et al., 2005), including human sperm (Bedu-Addo et al., 2007; Lawson et al., 2007), with a role primarily in the process of acrosomal exocytosis. Because Ca2+ has been observed to rise in the flagella of acrosome-reacted sperm as well as in the head, leading to an increase in intensity of hyperactivation (Suarez and Dai, 1995), it is possible that Ca2+ released from this store contributes in some way to hyperactivation.
The CatSper channels are confined to the principal piece of the flagellum, whereas the RNE Ca2+ store lies in close association with the mitochondria at the base of the midpiece mitochondrial sheath (Figs 2 and 3). It is not known whether the Ca2+ for hyperactivation normally comes from both the RNE and plasma membrane channels, or whether the RNE serves instead to modulate hyperactivated motility. Mouse sperm loaded with fluorescent Ca2+ indicator and treated with cell-permeant cyclic nucleotides or with alkaline high potassium medium to activate CatSper channels showed an instantaneous increase in Ca2+ throughout the principal piece which subsequently took 3–6 s to spread through the midpiece and reach the head. This response was not seen in sperm from CatSper null mutants (Xia et al., 2007). Due to the presence of RNE, mitochondria and Ca2+ buffers in the cytoplasm, the observed spread of increased Ca2+ to the head is highly unlikely to be solely the result of simple diffusion from the flagellar principal piece (reviewed in Clapham, 2007). Nevertheless, the participation of RNE Ca2+ stores in spreading the CatSper-induced increase or, for that manner, in normal physiological triggering of hyperactivation in vivo, has not been investigated.
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In intact sperm, as in many other cell types, cytoplasmic Ca2+ is maintained at physiologically appropriate levels by Ca2+-ATPases and Na+/Ca2+ exchangers, which pump Ca2+ out of the cell or into intracellular stores (reviewed in Jimenez-Gonzalez et al., 2006
; Clapham, 2007). The primary mechanism of removing excess Ca2+ from sperm is a plasma membrane Ca2+-ATPase (PMCA) (Wennemuth et al., 2003a, b; Harper et al., 2005; Jimenez-Gonzalez et al., 2006). PMCA has been localized to the principal piece of the flagellum (Wennemuth et al., 2003a, b; Okunade et al., 2004; Schuh et al., 2004), which is also the location of the CatSper Ca2+ channels (Carlson et al., 2005; Jin et al., 2007). Male mice that are null mutants for the gene encoding PMCA4 are infertile, because their sperm become immotile during the course of capacitation instead of hyperactivating (Okunade et al., 2004). The mitochondria of the immotile sperm show abnormal density patterns in transmission electron micrographs, indicative of Ca2+ overload (Okunade et al., 2004). Intracellular Ca2+ levels of motile null sperm were higher than those of wild-type sperm (Schuh et al., 2004).
In human sperm, a secretory pathway Ca2+-ATPase has been immunolocalized to the midpiece and rear head and suggested to play a role in clearance of Ca2+ released from the RNE store (Harper et al., 2005). There is also evidence for a Na+/Ca2+ exchanger in human sperm, localized primarily to the postacrosomal region and flagellar midpiece (Krasznai et al., 2006; Jimenez-Gonzalez et al., 2006). Its role in clearance of excess Ca2+ from the cytoplasm, at least in mouse sperm, is known to be minor compared with that of PMCA Ca2+ pumps (Wennemuth et al., 2003a, b).
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cAMP signaling activates motility and enhances beat frequency, but does not induce deep flagellar bending characteristic of hyperactivation |
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Activation of sperm motility is a prerequisite for hyperactivation, in the sense that sperm that cannot swim cannot become hyperactivated. Activation is dependent on cAMP produced by the form of adenylyl cyclase known as sAC or SACY. Sperm from SACY null mice are unable to activate fully, although they show some sluggish movement (Esposito et al., 2004
; Xie et al., 2006). The null sperm are also unable to undergo protein tyrosine phosphorylation associated with capacitation and do not hyperactivate (Hess et al., 2005; Xie et al., 2006). When sperm from SACY null mice are activated using cell-permeant cAMP-AM, they proceed to hyperactivate under capacitating conditions (Marquez and Suarez, 2008). Thus, cAMP produced by SACY is necessary to activate sperm and, in that sense, is a prerequisite for hyperactivation. SACY is stimulated by Ca2+ and HCO3– (Chen et al., 2000; Xie et al., 2006; Carlson et al., 2007). Stimulating SACY in sperm that are already motile increases flagellar beat frequency (Wennemuth et al., 2003a, b; Xie et al., 2006; Carlson et al., 2007). A detailed study showed that HCO3– stimulation of SACY in motile mouse sperm requires the presence of extracellular Ca2+, which acts upstream of HCO3–. Furthermore, the normal source of HCO3– is CO2 that diffuses into sperm (Carlson et al., 2007). The beat cross frequency of motile human sperm is also increased by HCO3– (Luconi et al., 2005); however, increased beat frequency does not constitute hyperactivation, which is instead characterized by an increase in flagellar bend amplitude. The increase in bend amplitude usually comes at the expense of beat frequency, because it takes the flagellum longer to generate a larger bend (Suarez et al., 1991; Mortimer et al., 1997).
The cAMP generated by SACY activates protein kinase A, which phosphorylates serine or threonine resides on proteins, thereby turning on a signaling pathway that leads to phosphorylation of tyrosine residues on other proteins. Increased protein tyrosine phosphorylation in flagella is associated with hyperactivated motility in hamster (Si and Okuno, 1999) and monkey sperm (Mahony and Gwathmey, 1999). Tyrosine phosphorylation has also been associated with heat-induced hyperactivation in human sperm (Chan et al., 1998). Tyrosine phosphorylation, dephosphorylation and rephosphorylation of an 80-kDa protein in hamster sperm flagella are associated with the acquisition, loss and reacquisition of temperature-dependent hyperactivation (Si, 1997). However, bull sperm do not hyperactivate when incubated under conditions that increase protein tyrosine phosphorylation and enable sperm to undergo the acrosome reaction; and furthermore, when uncapacitated bull sperm are treated with procaine or caffeine, they immediately hyperactivate without showing an increase in tyrosine phosphorylation (Marquez and Suarez, 2004). Thus, the role of tyrosine phosphorylated proteins is not entirely clear.
Generation of cAMP can also stimulate Ca2+ influx, through either cyclic nucleotide-gated Ca2+ channels (Wiesner et al., 1998) or CatSper channels (Xia et al., 2007) to contribute to hyperactivation.
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Increased ATP and PH are required by the axoneme to produce hyperactivation |
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When Triton X-100-demembranated bull sperm were reactivated in the presence of ATP and 400–1000 nM Ca2+, the flagella began to beat asymmetrically. However, to produce the deep flagellar bending characteristic of full-blown hyperactivation, higher levels of ATP were required in the reactivation solution than were required to produce activated motility, indicating an increased ATP requirement for hyperactivation (Ho et al., 2002
).
Lactate production plays a key role in providing ATP for motility in general and, consequently, for hyperactivation. A germ-cell-specific form of lactate dehydrogenase, LDH-C4, is responsible for most of the LDH activity in sperm (Odet et al., 2008). Male mice that are null mutants for Ldhc are infertile. The sperm activate normally, but, when incubated in capacitation medium, the null sperm show a decline in motility over time and hyperactivation never develops (Odet et al., 2008).
Hyperactivation of demembranated sperm requires a pH of 7.9–8.5, whereas activation can occur at a pH as low as 7.0, indicating that the cytoplasmic pH increases in the axonemal compartment of intact sperm at the time of hyperactivation (Ho et al., 2002). If so, then alkaline pH plays a double role in supporting hyperactivation, because CatSper channels are activated by alkaline intracellular pH (Kirichok et al., 2006). A rise in pH that activates CatSper channels would also directly stimulate hyperactivated bending at the axoneme (Fig. 2). Treating bull sperm with NH4Cl to raise intracellular pH stimulated a rise in intracellular Ca2+ and hyperactivation; furthermore, the NH4Cl treatment stimulated a more intense hyperactivation than the Ca2+ ionophore ionomycin, even though ionomycin produced a larger increase in intracellular Ca2+ (Marquez and Suarez, 2006). Intracellular pH increases during capacitation of mouse sperm (Zeng et al., 1996) and thus would stimulate hyperactivation by activating CatSper channels and triggering asymmetrical bending of the axoneme.
A weakly outwardly rectifying K+ current, dubbed KSper, has been detected in mouse sperm and proposed to be caused by the product of the testis-specific mSlo3 gene (Navarro et al., 2007). The efflux of K+ through this channel hyperpolarizes the plasma membrane and, in doing so, increases the driving force for Ca2+ influx through CatSper channels. Like CatSper activity, the KSper K+ current is stimulated by alkaline pH; therefore, efflux of H+ from flagella could affect Ca2+ influx directly through CatSper channels and indirectly through activation of KSper K+ currents (Navarro et al., 2007) (Fig. 2).
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Relationship of hyperactivation to capacitation |
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The physiological changes that confer on sperm the ability to fertilize are collectively called ‘capacitation’ (Yanagimachi, 1994
). These changes include hyperactivation and developing the capacity to undergo the acrosome reaction in response to specific triggers (referred to as ‘acrosomal responsiveness’). Although hyperactivation usually occurs in vitro at some point during the capacitation process, the pathways leading to hyperactivation and acrosomal responsiveness are not completely coupled. Boatman and Robbins (1991) found that HCO3– is essential for both acrosomal responsiveness and hyperactivation of hamster sperm in vitro, but hyperactivation requires higher levels of HCO3–. Hyperactivation can occur independently of acrosomal responsiveness in mouse and hamster sperm. Sperm from male mice with a t complex haplotype (tw32/+), a region of inversions in chromosome 17, showed hyperactivated motility prematurely when incubated under capacitating conditions, while acrosomal responsiveness occurred on schedule (Neill and Olds-Clarke, 1987; Olds-Clarke, 1989). In hamster sperm, hyperactivation develops fully in capacitation medium an hour or more before acrosome reactions are seen (Suarez and Dai, 1995). Procaine rapidly initiates hyperactivation in uncapacitated guinea pig and bull sperm (Mujica et al., 1994; Ho et al., 2002) and bull sperm hyperactivated by procaine do not undergo tyrosine phosphorylation associated with acrosomal responsiveness (Marquez and Suarez, 2004). Bull sperm incubated under conditions that promote acrosomal responsiveness do not hyperactivate (Marquez and Suarez, 2004). Thus, the processes of hyperactivation and development of acrosomal responsiveness are not completely tied to each other.
When human sperm are incubated in capacitation medium, an average of 10–20% develop motility patterns that look like hyperactivation (Burkman, 1984; Buffone et al., 2005).
Sperm from fertile men show higher levels of hyperactivation (12%) than sperm from asthenozoospermic infertility patients (4%) (Buffone et al., 2005). However, the levels shown by the normal samples are so low that we cannot be certain that incubation in capacitating medium is the optimal means of hyperactivating human sperm or if additional stimulatory factors play a role in hyperactivating sperm in vivo.
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Factors triggering hyperactivation in vivo are poorly understood |
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Unfortunately, the physiological trigger that switches on hyperactivation in vivo remains elusive nearly 40 years after hyperactivation was first reported by Yanagimachi (1970)
. Hyperactivation must occur at the right place and time to achieve fertilization. There is evidence that hyperactivated sperm cannot traverse the uterotubal junction (Gaddum-Rosse, 1981); therefore the oviduct is the best place to seek triggering molecules. The trigger could be secreted by the oviductal epithelium or introduced into the oviduct by the oocyte–cumulus mass. Hormones, ions and secretions in the oviductal luminal fluid vary during the estrous cycle (Nichol et al., 1992).
Human follicular fluid has a dose-dependent effect on flagellar beat frequency and hyperactivation (Yao et al., 2000). It was suggested that progesterone is the active factor, because it enhances hyperactivation (Sueldo et al., 1993). However, progesterone did not stimulate hyperactivation in at least one study (Kay and Robertson, 1998). Furthermore, the identity of the progesterone receptor is unknown (Modi et al., 2007) and localization of putative progesterone receptors is confined to the human sperm head (Blackmore and Lattanzio, 1991).
Cumulus cells that enter the ampulla with the oocyte may secrete signals for hyperactivation. Supernatant from the culture of cumulus oophorus cells increased curvilinear velocity and side-to-side movement of the heads of human sperm (Fetterolf et al., 1994).
However, despite evidence from in vitro experiments for a role of follicular fluid and cumulus in initiating hyperactivation, no specific signals have been unequivocally identified. Furthermore, there is evidence that sperm hyperactivate before cumulus and follicular fluid enter the oviduct. Hyperactivated sperm have been recovered from the rabbit oviduct before ovulation (Cooper et al., 1979; Overstreet and Cooper, 1979) and hyperactivated mouse sperm could be seen through the walls of transilluminated oviducts before ovulation (Suarez and Osman, 1987). On the other hand, steroid hormones in follicular fluid of antral follicles that are still in the ovary could reach sperm in the oviductal isthmus via vascular counter-current transfer from veins leaving the ovary to arteries supplying the wall of the isthmus (Hunter et al., 1983).
The oviductal epithelium could secrete hyperactivation-signaling molecules; however, none have been identified. Alternatively, there may be no specific macromolecular trigger, but rather a change in ionic environment, particularly an increase in the pH of oviduct fluid that activates the CatSper channels and raises intracellular pH to initiate hyperactivation. The pH in the lumen of the rhesus monkey oviducts was measured using miniaturized pH electrodes and found to be 7.1–7.3 during the follicular phase. At ovulation there was a sudden increase to 7.5–7.8, which was maintained throughout the luteal phase (Maas et al., 1977). This pH increase could possibly be the primary factor inducing hyperactivation in the oviduct.
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Hyperactivation may be modulated by chemotactic factors |
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Chemotaxis has been well documented in sperm of some marine invertebrates. Very low concentrations of specific peptides secreted by sea urchin oocytes attract sperm. In brief, binding of the peptide to sperm increases intracellular cyclic nucleotide levels, then intracellular Ca2+, which increases flagellar bend asymmetry and swimming path curvature (reviewed by Kaupp et al., 2008
).
Peptide ligands like those of sea urchin oocytes have not been identified in mammals, but there is evidence that odorant-like molecules function as chemoattractants to mammalian sperm. Antibodies to conserved amino acid sequences of odorant receptors specifically labeled the flagellar midpiece of mature dog and rat sperm, as well as the base of the flagellum of mature rat sperm (Vanderhaeghen et al., 1993; Walensky et al., 1995). Some of these antibodies also detected odorant receptors in western blots of protein extracts of hamster and human sperm (Walensky et al., 1995). A human odorant receptor specific to the testis was identified, cloned and functionally expressed in human embryonic kidney cells, where stimulation by specific odorant molecules produced Ca2+ signals (Spehr et al., 2003). Human sperm respond to the floral odorant bourgeonal by producing Ca2+ signals and orienting in a gradient of the odorant (Spehr et al., 2003, 2004). Thus, it is thought that a molecule resembling bourgeonal guides human sperm to the oocyte in vivo. Such a molecule is currently the object of an intense search.
Human sperm have also been observed responding to gradients of progesterone with oscillations in intracellular Ca2+ superimposed on a rise in Ca2+. The flagella of responding sperm showed temporary increases in bend amplitude that corresponded to the oscillatory Ca2+ peaks (Harper et al., 2004). Because cumulus cells secrete progesterone, a gradient could develop in the vicinity of the cumulus mass in the oviduct. Nevertheless, despite functional evidence for its existence, a progesterone receptor has yet to be identified in human sperm (Correia et al., 2007; Modi et al., 2007). The cytokine Rantes has also been implicated in human sperm chemotaxis (Isobe et al., 2002) and its receptors have been localized to the sperm heads (Muciaccia et al., 2005). For reviews on sperm chemotaxis, see Eisenbach (2007) and Kaupp et al. (2008).
The relationship of the signaling pathways that switch on hyperactivation and chemotaxis is currently a mystery. There is evidence that both hyperactivation and chemotactic responses involve a rise in Ca2+; however, the Ca2+ rise produced by activating CatSper channels to induce hyperactivation in mouse sperm originates in the principal piece of the flagellum (Xia et al., 2007), while the Ca2+ rise detected in response to the odorant bourgeonal originates in the midpiece of human sperm (Spehr et al., 2004).
Because hyperactivation occurs in the oviduct far from the oocyte and even before ovulation (Cooper et al., 1979; Overstreet and Cooper, 1979; Suarez and Osman, 1987), it is likely that sperm are already hyperactivated when they receive odorant signals. Perhaps chemotactic factors act on hyperactivated sperm to trigger brief releases of Ca2+ from the RNE store that modulate the flagellar beating pattern just long enough to re-direct the path of the sperm.
Chemotactic factors could serve to direct sperm toward the ampulla, toward the cumulus mass in the ampulla and/or toward the oocyte within the cumulus mass. In mice, the cumulus mass fills the entire lumen in a substantial region of the oviductal ampulla and makes an easy target for sperm; however, mouse sperm may require guidance to locate oocytes within the mass. In humans, the cumulus mass is a very small target for sperm, because it does not fill the ampullar lumen and the lumen is divided into complex branched channels by mucosal folds (Fig. 4). Without guidance by chemotaxis, human sperm could easily pass by the cumulus mass.
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Last word: what is hyperactivation in human sperm and how can we assess it? |
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Numerous studies in various species have indicated that hyperactivated motility is critical to achieving fertilization in vivo, because it assists sperm in reaching the oocyte through the mucus-filled lumen of the oviduct and then enables sperm to penetrate the zona pellucida. Thus, measuring the ability of human sperm to hyperactivate in response to physiological stimuli can be a useful assay to include in the battery of tests for infertility, particularly for those clinicians who believe that intracytoplasmic sperm injection should be used only after exhausting other treatments, including in vitro fertilization.
Although human sperm have been reported to swim in patterns characteristic of hyperactivation in vitro, the motility of human sperm has not been video recorded within the oviduct or even in flushings of the oviduct. Thus we cannot be certain of what exactly constitutes hyperactivation in human sperm. Given the ethical and technical challenges for getting this information, identifying hyperactivation in clinical samples will have to depend on information learned from studies of model species. Hyperactivation, as defined from studies of model species, has been observed in human sperm incubated under capacitating conditions (Morales et al., 1988; Mortimer and Mortimer, 1990; Mortimer and Swan, 1995b); however, there is no standardization of capacitating conditions among published studies nor is there standardization of CASA settings used to detect hyperactivation.
Incubation of human sperm in capacitation medium leads to a gradual increase in incidence of hyperactivation, usually with an average maximum of 20% or less. If specific physiological triggers for hyperactivation were found in model species that could be used on human sperm to produce a rapid and more substantial response, this would enable the development of a fertility assay that would provide higher resolution of the level of fertility of a sample.
In conclusion, hyperactivation is critical to fertilization and reliable tests are needed for assessing the ability of human sperm samples to undergo hyperactivation normally.
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Funding |
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Funding for work by the author that has been described in this review was supported by the US National Science Foundation, and the United States Department of Agriculture Cooperative State Research, Education, and Extension Service National Research Initiative.
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Acknowledgements |
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Dr George Ignotz kindly reviewed the manuscript.
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