Calcium Influx and Male Fertility in the Context of the Sperm Proteome: An Update

Rahman, Md Saidur; Kwon, Woo-Sung; Pang, Myung-Geol

doi:https://doi.org/10.1155/2014/841615

BioMed Research International

On this page

Abstract Introduction Acknowledgments References Copyright Related Articles

Special Issue

New Advances in Reproductive Biomedicine

View this Special Issue

Review Article | Open Access

Volume 2014 | Article ID 841615 | https://doi.org/10.1155/2014/841615

Calcium Influx and Male Fertility in the Context of the Sperm Proteome: An Update

Md Saidur Rahman,¹Woo-Sung Kwon,¹and Myung-Geol Pang¹

Academic Editor: Jeroen Krijgsveld

Received17 Dec 2013

Accepted14 Jan 2014

Published27 Apr 2014

Abstract

Freshly ejaculated spermatozoa are incapable or poorly capable of fertilizing an oocyte. The fertilization aptness of spermatozoa depends on the appropriate and time-dependent acquisition of hyperactivation, chemotaxis, capacitation, and the acrosome reaction, where calcium (Ca²⁺) is extensively involved in almost every step. A literature review showed that several ion channel proteins are likely responsible for regulation of the Ca²⁺ uptake in spermatozoa. Therefore, manipulation of the functions of channel proteins is closely related to Ca²⁺ influx, ultimately affecting male fertility. Recently, it has been shown that, together with different physiological stimuli, protein-protein interaction also modifies the Ca²⁺ influx mechanism in spermatozoa. Modern proteomic analyses have identified several sperm proteins, and, therefore, these findings might provide further insight into understanding the Ca²⁺ influx, protein functions, and regulation of fertility. The objective of this review was to synthesize the published findings on the Ca²⁺ influx mechanism in mammalian spermatozoa and its implications for the regulation of male fertility in the context of sperm proteins. Finally, Pathway Studio (9.0) was used to catalog the sperm proteins that regulate the Ca²⁺ influx signaling by using the information available from the PubMed database following a MedScan Reader (5.0) search.

1. Introduction

Spermatozoa are atypical cells with peculiar functionality: they are produced in one organism and released, and then they invade another organism and deliver their genetic material into a host cell to produce offspring by sexual reproduction. It is a well-known fact that only about 1 in 25,000 spermatozoa finally reaches the fallopian tube and gets the opportunity to fertilize an oocyte. In the mid-20th century, it had been claimed that mammalian spermatozoa are unable to fertilize an oocyte before achieving functional maturation, which occurs during their journey through the female reproductive tract for a finite period of time [1, 2]. This fundamental maturational process is chiefly regulated by numerous signaling cascades, and calcium (Ca²⁺) plays a dynamic role in this process, as an intracellular second messenger. Several studies have hypothesized that elevation of sperm intracellular Ca²⁺ ()/Ca²⁺ influx regulates motility, hyperactivation, chemotaxis, capacitation, and the acrosome reaction and facilitates the spermatozoa reaching and fertilizing of an oocyte [3–8]. Therefore, understanding the mechanism that regulates the Ca²⁺ influx in spermatozoa is a matter of utmost importance.

Previous studies have shown that the Ca²⁺ entry mechanisms are regulated via numerous Ca²⁺ permeable channel proteins in spermatozoa [6, 9, 10]. Therefore, the factors that regulate the functions of those channels will ultimately help us understand how male fertility is regulated. Recent applications of proteomic approaches such as two-dimensional polyacrylamide gel electrophoresis, mass spectrometry, and differential in-gel electrophoresis have yielded the identification of several sperm-specific proteins [11, 12]. These discoveries have provided new insight into protein functions and enabled us to recognize diverse sperm-specific processes in order to differentiate normal from abnormal spermatozoa [11]. Mature spermatozoa are widely known to be silent in both transcription and translation [11, 13, 14] or poorly capable of translation [15]; therefore, studies on individual sperm proteomes have described the importance of spermatozoal posttranslational modifications and their ability to induce physiological changes as a prerequisite for successful fertilization.

Torres-Flores et al. [16] have shown that human spermatozoa exposed to the phosphodiesterase inhibitor papaverine cause activation of protein kinase A (PKA) and stimulate the progesterone-induced Ca²⁺ influx via the cyclic adenosine monophosphate- (cAMP-) dependent pathway. Although these authors did not evaluate the relationship between in vitro fertility and Ca²⁺ influx, changes in intracellular pH and increased tyrosine phosphorylation ultimately provide a potential clue regarding sperm fertility competence. In another study, to evaluate hamster spermatozoa capacitation capability, comparative association was observed between pyruvate dehydrogenase A, Ca²⁺ influx, cAMP, and reactive oxygen species [17]. Additionally, Breitbart et al. [18] reported that polymerization of globular- (G-) actin to filamentous- (F-) actin occurs during capacitation. As capacitation and the acrosome reaction are Ca²⁺-mediated events [4, 5], one can, without considering further signaling cascade, assume that remodeling the actin structure might be linked with the regulation of Ca²⁺ influx in spermatozoa.

Recently, in our laboratory, we found that the manipulation of sperm proteins such as ubiquinol-cytochrome-c reductase core protein 2 (UQCRC2) [39], voltage-dependent anion channels proteins (VDACs) [4], and arginine vasopressin [5] could control the Ca²⁺ influx in spermatozoa and regulate capacitation, the acrosome reaction, and fertility. Therefore, design and construction of a similar study with most of the identified sperm proteins available from several protein databases might provide a more realistic insight into the Ca²⁺ influx, protein functions, and fertility. The present work reviews the latest information published by other laboratories as well as our research team on the aforementioned aspects of spermatozoa and their potential implications for diagnosis and prognosis of male fertility.

2. Mechanism of Ca²⁺ Influx in Mammalian Spermatozoa

The ultimate goal of fertilization of mammalian sperm is to fuse with and deliver their genetic materials into an oocyte [2, 40, 41]. For fertilization to occur completely, the spermatozoa must experience various obstacles both in vitro and in vivo [40, 41]. Ca²⁺ ions act as central signaling molecules; once they enter the spermatozoa, they exert allosteric regulatory effects on enzymes and many proteins [10, 21, 42]. Indeed, numerous elegant research findings have contributed significantly to our understanding of the molecular signaling of Ca²⁺ influx, especially through monitoring the activity of individual cells. However, most of the studies are discrete and often do not represent a cumulative idea. This section presents a compilation of some basic information regarding the Ca²⁺ entry mechanism into mammalian spermatozoa by recapitulating scientific evidence.

The literature reviewed shows that the primary source of Ca²⁺ for spermatozoa is the external environment: the fallopian tube in the female reproductive tract (in vivo) and culture media (in vitro) [8], and simultaneously increasing regulates the release of Ca²⁺ into the cell. Therefore, how Ca²⁺ crosses into cells through the sperm plasma membrane is a matter of paramount importance. In eukaryotic cells, the Ca²⁺ influx occurs through specific Ca²⁺ permeable ion channel proteins located on the plasma membrane [43, 44] such as classical voltage-gated (high and low) Ca²⁺ (), transient receptor potential (TRP), and cyclic nucleotide-gated (CNG) channels [9]. Recently, Ren and Xia have proposed four criteria to identify sperm ion channel proteins: detectability in sperm, preferably with knockout sperm as a negative control; ability to produce ion channel current detectable by patch-clamp recording; blocking of the channels that impairs normal sperm function; and mutations of gene encoding the ion channel proteins leading to sperm malfunctions [10].

The CatSper family of channels is the newest and only family of voltage-gated Ca²⁺ channels that meets most of the aforementioned criteria and essentially regulates Ca²⁺ entry into cells and is therefore crucial for sperm fertility [9, 45]. Four pore-forming CatSper channel proteins, CatSper 1–4, and at least two auxiliary subunits, CatSperβ and CatSperγ, have been identified in a wide range of animals, including humans and mice [46, 47]. Physiologically, CatSper members are permeable to Ca²⁺,whereas the CatSper knockdown sperm does not have the channel current that is detected in the principal piece of wild-type sperm [20, 48]. Most of the channel proteins, including CatSper members, have been identified in the principal piece of spermatozoa [20, 46, 47, 49] (Figure 1). Although the explanation of such subcellular localization is still debated, it might be because of interactions among the channel proteins and with the auxiliary subunits, although a further study is needed to resolve this issue. Collectively, these proteins play a key role in various cellular processes via regulation of the membrane potential and intracellular ionic balance. Carlson et al. [50] and Quill et al. [51] have conclusively proved that CatSper1 and CatSper2 null mice are sterile owing to their inability to generate the sperm-hyperactivated motility prerequisite for penetration of an oocyte extracellular matrix. In effect, the complete or partial absence of single or multiple Ca²⁺ channels is responsible for infertility or subfertility, although their underlying signaling cascade has not been properly studied.

Figure 1

Possible signal transduction mechanisms of mammalian sperm Ca²⁺ influx through the Ca²⁺ permeable channel proteins. Previously published studies were used as references to summarize the list of channel proteins in spermatozoa. The channel proteins are localized mainly in the principle piece of spermatozoa. The follicular fluid and several factors in the fallopian tube (in vitro media) stimulate the receptors for spermatozoa Ca²⁺ influx. Ca²⁺ influx in spermatozoa is principally regulated by CatSper channels; however, the possible interaction between other channels that are responsible for controlling the opening of CatSper and allowing the Ca²⁺ into cells is indicated by arrow signs (red circle). The different channel proteins that are depicted in the diagram include the Na⁺-coupled transporter (NBC) family, soluble adenylyl cyclase (sACY), adenosine triphosphate (ATP), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), cyclic nucleotide-gated ion channel (CNG), hyperpolarization-activated cyclic nucleotide-gated channel (HCN), zona pellucida (ZP), the voltage-gated proton channel (Hv1), glutamate receptor family class-C (GPCRC), and an unknown mechanism (?).

Previously, it has been reported that CatSper-dependent increases of in spermatozoa are induced by several psychological stimuli such as cyclic nucleotides (e.g., cAMP and cGMP) [29, 30, 52], soluble adenylyl cyclase [29, 52], zona pellucida glycoprotein [34, 35, 38], serum albumin [37, 38], secretion of cumulus oophorus [38], intracellular alkalization [3, 53], and pH [6, 21]. A recent study showed that endocrine disruptors such as p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) promoted Ca²⁺ entry into spermatozoa by activating CatSper channels, even at a physiological concentration [36]. In addition, several other components are also known to play an important role in Ca²⁺ influx mechanisms in mammalian spermatozoa by regulating the opening of CatSper members, including the flagellar voltage-gated proton channel (Hv1) [21], Ca²⁺-ATPase pump [33], several cyclic nucleotide-gated ion channels (CNG) [27, 54], hyperpolarization-activated cyclic nucleotide-gated (HCN) channels [27], and G-protein coupled receptors (GPCRs).

A hypothetical signaling cascade of Ca²⁺ influx pathways and interaction of several channel proteins is depicted in Figure 1. Although the functions of several ion channel proteins together with their concurrent relationship with numerous stimuli have been well studied [21, 27, 38], several fundamental questions remain unanswered; for example, how do these channels/stimuli regulate the Ca²⁺ influx during spermatozoa processes such as capacitation, the acrosome reaction, and fertilization? Do they work alone or together with other channel proteins to regulate Ca²⁺ influx? Moreover, which other parameters that remain undetected could have an effect on Ca²⁺ influx? Therefore, future research should focus on resolving these issues. Table 1 summarizes the proposed effect of Ca²⁺ ion channels and their physiological role that ultimately helps Ca²⁺ influx into mammalian spermatozoa.

3. Effect of Ca²⁺ Influx on Male Fertility

Ca²⁺ triggers multiple physiological events in spermatozoa, such as hyperactivation, chemotaxis, capacitation, and the acrosomal reaction, all of which are essential for successful fertilization. In mammalian spermatozoa, numerous Ca²⁺ permeable channel proteins control intracellular pH, and the pH-dependent Ca²⁺ influx is measured by the whole-cell patch clamp technique [9, 20]. A review of the literature showed that a potential functional interaction exists between the sperm proteins and Ca²⁺ permeable channel proteins, thus modulating the Ca²⁺ influx mechanism [4, 5, 39] and playing a vital role in adjusting male fertility. However, the mechanism by which Ca²⁺ triggers intracellular signaling to regulate physiological events in spermatozoa and the role of sperm proteins in adjustment of Ca²⁺ influx into cells remains unclear. This topic is emphasized below.

3.1. Ca²⁺ Influx, Sperm Hyperactivation, Chemotaxis, and Protein Functions

In general, mature spermatozoa are held immotile within the epididymis. However, they quickly begin to swim following release. This is known as activation of motility and is characterized by symmetrical flagellar beats [55, 56]. The terms sperm activation and hyperactivation have quite different meanings. The spermatozoa become hyperactivated when the amplitude of the flagellar bend increases and produces a highly asymmetrical beat. In vivo, hyperactivation of spermatozoa facilitates the release of sperm from oviductal storage and boosts them through mucus in the oviductal lumen and matrix of the cumulus oophorus during fertilization [7]. In contrast, chemotaxis is a form of sperm movement in which spermatozoa move toward a concentration gradient of a chemoattractant released from the oocyte [57, 58]. However, the molecular event that characterizes spermatozoa chemotaxis is only partially known [57].

There is strong evidence to support that sperm hyperactivation and chemotaxis are required for penetrating the zona pellucida [48, 57, 59, 60]. Incubation of spermatozoa with an extracellular Ca²⁺ source induces hyperactivation in mammalian spermatozoa [61, 62] and chemotaxis in starfish [57]. In addition, measuring cytoplasmic Ca²⁺ levels by using the fluorescent Ca²⁺ indicator indo-1 proved that spermatozoa hyperactivation is potentially regulated by Ca²⁺ influx. However, it is unknown whether Ca²⁺ influx independently induces hyperactivation/chemotaxis in mammalian spermatozoa. Ho and Suarez [56] proposed that sperm hyperactivation induced by Ca²⁺ influx is mainly pH-dependent because sperm require a pH of 7.9–8.5 for hyperactivation, whereas activation can occur at a . The proposed model of Ca²⁺-induced hyperactivation is represented in Figure 2.

Figure 2

Schematic diagram showing the mechanism of Ca²⁺ regulated hyperactivation, capacitation, and the acrosome reaction of spermatozoa, which are three principal events of fertilization. Ca²⁺ together with ZP3 (zona pellucida glycoprotein-3) exhibits the most important role in sperm binding and acrosomal reaction. Ca²⁺ triggers the zona pellucida (ZP) receptors of cell membrane that activate G-proteins in the sperm head. Activated G-proteins stimulate the H⁺ transporter to increase intracellular pH, ultimately inducing the acrosomal reaction and hyperactivation by catalyzing the acrosomal enzymes [91]. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are produced from adenosine triphosphate (ATP) owing to enzymatic catalysis by soluble adenylate cyclase (sAC) and guanylate cyclase (sGC), respectively, in mature spermatozoa. The bicarbonate ions activate the sAC; however, follicular fluid also stimulates the sAC through release of Ca²⁺ ions via the CatSper channel (principal piece). However, G-protein mediated signal transduction activates sAC and phospholipase-C (PLC) that ultimately causes tyrosine phosphorylation [51, 92], which is responsible for events such as capacitation and the acrosomal reaction. Likewise, extracellular signals such as nitric oxide (NO) and carbon monoxide (CO) stimulate membrane-bound GC (mGC) and sGC, respectively, to synthesize cGMP. Increases in cGMP level evoke a concomitant increase in cAMP by inhibiting its PDE3. However, the increased Ca²⁺ level can also directly catalyze cAMP [93, 94]. Activated sAC, sGC, and PLC stimulate the generation of the second messengers’ inositol trisphosphate (IP3) like cAMP, cGMP. The IP3 binds to the IP3 receptor (IP3R) to increase via the release of the storage ions. Concurrently, the second messengers activate protein kinases (PKA, PKC, and PKG), in turn gating ions through the T-type calcium channels, cyclic-nucleotide gated ion channel (CNG), and so on, that together with the activation of protein tyrosine kinases (PTK) and serine/threonine protein kinase (STK) cause increased protein phosphorylation [93, 94]. Additionally, the CatSper Ca²⁺ activates calmodulin (Calm), phospholipase-A (PLA), and phospholipase-D (PLD) with increased generation of other second messengers during the acrosome reaction. Ca²⁺ influx together with increased protein phosphorylation brings about the capacitation response that is responsible for the waveform asymmetry of motility termed hyperactivation during fertilization. Both hyperactivation and the acrosomal reaction boost flagellar beating, ultimately resulting in the penetration of the outer egg coat and subsequent fertilization of the mature ovum [91–95].

It has recently been found by our laboratory that treatment of mouse spermatozoa with nutlin-3a, a small molecule antagonist of the mouse double minute 2 repressor, potentially downregulates the functions of the ubiquinol-cytochrome-c reductase complex component UQCRC2 and correlated with significantly reduced and sperm hyperactivation. This study provided insight that the Ca²⁺ influx in spermatozoa is partially regulated by UQCRC2 protein. Kwon et al. [4] reported that blocking VDAC with 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) significantly decreased sperm hyperactivation. A significant decrease in was observed in (−) DIDS conditions, while significantly increased in (−) DIDS, regardless of Ca²⁺. Simultaneously, a significantly elevated was observed in (+) Ca²⁺. This study provides strong evidence that the modulation of Ca²⁺ influx by VDACs is pH-dependent, which is consistent with the result of a previous study by Ho and Suarez [56]. Moreover, another study proposed that deamino [Cys 1, d-ArgS] vasopressin (dDAVP), an AVPR2 agonist, significantly decreased sperm motility and intracellular pH, but, interestingly, it increased by regulating the function of arginine vasopressin in mice spermatozoa. However, it remains to be clarified as to why spermatozoa motility is decreased even in increased conditions.

On the basis of the findings of the aforementioned studies, it is tempting to hypothesize that spermatozoa hyperactivation is mostly controlled by Ca²⁺ influx. However, potential interactions exist between protein functions. Therefore, Ca²⁺ influx, protein interaction, and hyperactivation might give numerous different annotations of upcoming research in this field. We have illustrated a schematic representation of different signaling pathways involving sperm proteins by using Pathway Studio. These proteins exhibit significant modifications to induce sperm hyperactivation and chemotaxis in spermatozoa by regulating Ca²⁺ influx (Figure 3).

3.2. Ca²⁺ Influx versus Capacitation, the Acrosomal Reaction, Fertilization, and Sperm Proteome

Mammalian fertilization is a species-specific episode that is accomplished by a complex set of molecular events. To fertilize an oocyte, multiple extreme changes occur in spermatozoa that begin from its formation in the testes of the male reproductive tract to its penetration and fusion with an egg in the female reproductive tract. Although spermatozoa are motile as well as morphologically normal after ejaculation, they are unable to fertilize an oocyte [59]. They gain the fertilization ability only after educating in the female reproductive tract [40], and the modifications that spermatozoa experience during this time are collectively known as “capacitation.” Only capacitated spermatozoa can undergo the acrosome reaction through binding to the egg zona pellucida, and they finally become capable of penetrating and fertilizing the egg [4, 18, 39].

The term “capacitation” was proposed by Austin in 1952 [1], although this concept was initially described by both Chang and Austin in 1951 [2, 41]. In fact, in vivo capacitation takes place in the female reproductive tract; however, it is also possible to capacitate spermatozoa in vitro by using particular media containing appropriate electrolytes and pH [2]. In an elegant review, Visconti summarized that the early stage of capacitation mainly comprises the bicarbonate-mediated activation of sperm motility, whereas the late stages include intracellular alkalinization, increase in protein tyrosine phosphorylation, and preparation for the acrosomal reaction [63]. These temporal differences in capacitation and the acrosome reaction require numerous mechanisms, and Ca²⁺ influx plays a significant role in the process [63, 64]. Fraser [65] reported that capacitation is a comparatively slow event that requires several hours to complete and is mainly regulated by a modest rise in , whereas the acrosome reaction is an exocytosis process that occurs very rapidly (within a minute) and is triggered by a large influx of [65, 66].

Although the biochemical phenomenon of Ca²⁺ regulated capacitation and the acrosome reaction have been known for the last two decades, the molecular basis of this process is still poorly understood. For capacitation, the cholesterol influx initially stimulates the elevation of and bicarbonate into the spermatozoa and finally activates PKA and tyrosine phosphorylation, respectively, via the production of the cAMP [66–68]. In addition, binding to the zona pellucida causes additional activation of cAMP/PKA and protein kinase C (PKC) [68–70]. Spermatozoa need influx to proceed further, and they are believed to be activated by PKC through the opening of the calcium channels. Interestingly, PKA together with a secondary messenger, inositol trisphosphate, activates calcium channels localized in the outer acrosomal membrane and increases the calcium concentration in the cytosol. Further increase of cytosolic Ca²⁺ influx occurs through a store-operated calcium entry mechanism in the plasma membrane, resulting in further depletion of Ca²⁺ in the acrosome [68, 69].

In support of the aforesaid studies, several recent studies on the same topic have also hypothesized that, after the morphological maturation of spermatozoa for sperm-oocyte fusion, decreases because acrosome-reacted spermatozoa release a substantial amount of Ca²⁺ from their inner cell layers [71, 72]. Ca²⁺-mediated capacitation and the acrosome reaction have been illustrated in Figure 2 for better understanding. However, for a more in-depth understanding, we recommend reading some excellent reviews on this topic [63, 67, 73–77].

A review of the literature showed that several sperm proteins potentially regulate the Ca²⁺-dependent capacitation and the acrosome reaction in mammalian spermatozoa [4, 5, 39]. However, how these proteins regulate the Ca²⁺ influx in spermatozoa is a matter that remains to be elucidated. Breitbart et al. [18] reported that formation of F-actin mostly depends on PKA, protein tyrosine phosphorylation, and phospholipase D activation during capacitation. Ca²⁺ is one of the principle regulators of capacitation, and it is therefore tempting to hypothesize that organizational modification of F-actin in spermatozoa together with interacting with other sperm proteins has potential influence on Ca²⁺ influx. A similar finding has been established more precisely by another study [78], where boar sperm capacitation was studied by combined application of computational and experimental approaches. These authors reported that the boar spermatozoa capacitation network contains several connecting cascades, whereas only three nodes bound to all the subcellular compartments are involved in spermatozoa postejaculatory signaling, such as , ATP, and actin polymerization. Removal of the actin polymerization node from this aforesaid network causes disorganization of the network topography and affects capacitation, and this has been confirmed by zona pellucida-induced capacitation and the acrosomal reaction in an in vitro demonstration [78].

In another study, Patrat et al. [79] showed that progesterone (P₄) that is secreted by cumulus cells directly acts on the sperm plasma membrane and triggers the intracellular signals and enzymatic pathways involved in the acrosome reaction. P₄ regulates the acrosome reaction and is mediated by a compulsory Ca²⁺ increase. This study found that P₄ induced the activation of Gi/Go protein-coupled and protein tyrosine kinase receptors, and it affected capacitation and the acrosome reaction. In contrast, Ca²⁺ regulated exocytosis of spermatozoa requires active acrosomal proteins such as N-ethylmaleimide-sensitive factor (NSF) [66]. Additionally, the same research team showed that the ras-related protein Rab-3A (RAB3A) is also necessary for Ca²⁺-dependent exocytosis. Interestingly, Rab3A activation of acrosomal exocytosis requires active NSF. Therefore, protein-protein interaction might also play a potential role in regulating Ca²⁺ influx. All of these observations seem to be consistent with the idea that Ca²⁺ functions are regulated by sperm proteins during fertilization. However, the key question is how do these proteins modify Ca²⁺ influx in spermatozoa?

Recently, in our laboratory, we used mice spermatozoa to evaluate the interrelationship of proteins related to Ca²⁺ influx, including UQCRC2 [39], arginine vasopressin [5], and VDACs [4], and evaluate their effects on capacitation and the acrosome reaction. It is likely that a sustained phase of Ca²⁺ is required for fertilization and might be regulated by the complex interaction of numerous sperm proteins. Therefore, studies to identify proteins that might have the ability to induce such a change are worth undertaking. Application of Pathway Studio helped us represent over 40 proteins that are potentially implicated in Ca²⁺ mediated regulation of capacitation, the acrosome reaction, and male fertility (Figure 4).

3.3. Ca²⁺ Influx and Postfertilization Egg Activation in Context of Sperm Proteome

Ca²⁺ influx in spermatozoa is not only important for sperm maturation, but it is also equally important for activation and development of the oocyte. A study of egg activation by Ca²⁺ was conducted by Steinhardt and colleagues in 1974 and showed remarkable findings [80]. Steinhardt et al. [80] reported that administration of Ca²⁺ ionophores induced the early events of hamster egg activation. Thus far, it has been shown that the eggs of almost all species are activated by an increase in Ca²⁺ oscillation by spermatozoa during fertilization [81, 82]. However, how the spermatozoa trigger the oocyte Ca²⁺ oscillation remains to be elucidated. Several hypotheses have been proposed to describe these mechanisms [83–86].

It has been reported previously [83] that the spermatozoa introduce Ca²⁺ influx into oocytes by a specific protein called oscillogen in hamsters. Recent studies have shown that phospholipase C zeta (PLCζ), a novel sperm-specific agent, is responsible for induction of Ca²⁺ oscillation in eggs after sperm-egg membrane fusion [87–89]. According to this mechanism, the sperm protein PLCζ causes the release of in eggs and is mediated via inositol 1,4,5-trisphosphate (InsP₃) receptors (hypothetical depiction in Figure 5). Even when the InsP₃ or its derivatives are injected into unfertilized, mature eggs, oscillation occurs due to the unique feedback properties of the InsP₃ receptors in mouse eggs [90]. However, it is still unknown whether there are any other factors/proteins available in spermatozoa that also have similar effects. We illustrated the relevant signaling and metabolic pathways by using sperm proteins to facilitate the understanding of the mechanisms behind Ca²⁺ mediated activation of oocytes (Figure 6).

Figure 5

Schematic representation showing the Ca²⁺ influx mechanism in mammalian eggs stimulated by mature spermatozoa. Spermatozoa donate the phospholipase C isoform zeta (PLCζ) protein within a few minutes of sperm-egg fusion (represented by green color circle). Inositol 1,4,5-trisphosphate (InsP₃) is produced due to the hydrolysis of PLCζ, which subsequently triggers the nsP₃ receptor-mediated Ca²⁺ release (indicated by red color circle) from the endoplasmic reticulum of the oocyte. Simultaneously, the increased cytoplasmic Ca²⁺ leads to further PLCζ stimulation, leading to the positive feedback loop of Ca²⁺ and InsP₃ rise. The hypothesis has been modified from Swann [96] and Swann et al. [97].

4. Future Prospects

The maturational events of mammalian spermatozoa are strictly regulated through the well-coordinated Ca²⁺ influx. It is the central regulator of many key activities in spermatozoa, all of which are necessary for fertilization. However, our current understanding at the molecular level concerning Ca²⁺ signaling in the spermatozoa is insufficient. Therefore, a better understanding of such an event can provide a more complete comprehension of Ca²⁺ regulated sperm functions and fertility optimization.

A large number of Ca²⁺ permeable ion channel proteins have been identified [10, 43] that collectively regulate the Ca²⁺ influx mechanism in spermatozoa. Although the recent application of patch-clamp recordings of channel current significantly improves our understanding of the functions of these channel proteins, several basic aspects remain unsolved, such as identifying the functions of individual channels in spermatozoa and how these channels coordinate Ca²⁺ influx. Therefore, production of knockdown animals and using them as negative controls compared with their wild counterparts might provide more specific ideas about channel functions. CatSper is the one of the well-studied channel proteins [10] and the functions of different pore-forming CatSper channels (1–4) and auxiliary subunits (CatSperβ and CatSperγ) remain a matter to be elucidated.

A literature review found that the Ca²⁺ influx mechanism in spermatozoa is regulated by several physical stimuli, although the underlying mechanism is less clearly defined. Protein-protein interactions also potentially regulate the Ca²⁺ uptake mechanism in spermatozoa. Although recently applied proteomic approaches have identified several sperm-specific proteins, their functions in Ca²⁺ regulation and interaction with channel proteins are unclear. Therefore, future research should target this topic to provide a robust understanding of Ca²⁺ and male fertility in both humans and other animal species.

Conflict of Interests

The authors have declared there is no conflict of interests that could be perceived as prejudicing the impartiality of this paper.

Acknowledgments

This study was financially supported by the Cooperative Research Program for Agriculture Science and Technology Development (Project no. PJ008415), Rural Development Administration, Republic of Korea. Md Saidur Rahman was supported through the “Chung-Ang University Young Scientist Scholarship (CAYSS),” Chung-Ang University, Republic of Korea.

References

C. R. Austin, “The capacitation of the mammalian sperm,” Nature, vol. 170, no. 4321, p. 326, 1952.
View at: Google Scholar
M. C. Chang, “Fertilizing capacity of spermatozoa deposited into the fallopian tubes,” Nature, vol. 168, no. 4277, pp. 697–698, 1951.
View at: Publisher Site | Google Scholar
N. Mannowetz, N. M. Naidoo, S.-A. Choo, J. F. Smith, and P. V. Lishko, “Slo1 is the principal potassium channel of human spermatozoa,” eLife, vol. 2, Article ID e01009, 2013.
View at: Publisher Site | Google Scholar
W.-S. Kwon, Y.-J. Park, A. M. El-Sayed, and M.-G. Pang, “Voltage-dependent anion channels are a key factor of male fertility,” Fertility and Sterility, vol. 99, no. 2, pp. 354–361, 2013.
View at: Publisher Site | Google Scholar
W.-S. Kwon, Y.-J. Park, Y.-H. Kim, Y.-A. You, I. C. Kim, and M.-G. Pang, “Vasopressin effectively suppresses male fertility,” PLoS ONE, vol. 8, no. 1, Article ID e54192, 2013.
View at: Publisher Site | Google Scholar
P. V. Lishko and Y. Kirichok, “The role of Hv1 and CatSper channels in sperm activation,” The Journal of Physiology, vol. 588, no. 23, pp. 4667–4672, 2010.
View at: Publisher Site | Google Scholar
S. S. Suarez, “Control of hyperactivation in sperm,” Human Reproduction Update, vol. 14, no. 6, pp. 647–657, 2008.
View at: Publisher Site | Google Scholar
C. Foresta and M. Rossato, “Calcium influx pathways in human spermatozoa,” Molecular Human Reproduction, vol. 3, no. 1, pp. 1–4, 1997.
View at: Google Scholar
Y. Kirichok, B. Navarro, and D. E. Clapham, “Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca²⁺ channel,” Nature, vol. 439, no. 7077, pp. 737–740, 2006.
View at: Publisher Site | Google Scholar
D. Ren and J. Xia, “Calcium signaling through CatSper channels in mammalian fertilization,” Physiology, vol. 25, no. 3, pp. 165–175, 2010.
View at: Publisher Site | Google Scholar
M. S. Rahman, J.-S. Lee, W.-S. Kwon, and M.-G. Pang, “Sperm proteomics: road to male fertility and contraception,” International Journal of Endocrinology, vol. 2013, Article ID 360986, 11 pages, 2013.
View at: Publisher Site | Google Scholar
Y.-J. Park, W.-S. Kwon, S.-A. Oh, and M.-G. Pang, “Fertility-related proteomic profiling bull spermatozoa separated by percoll,” Journal of Proteome Research, vol. 11, no. 8, pp. 4162–4168, 2012.
View at: Publisher Site | Google Scholar
M. A. Baker, B. Nixon, N. Naumovski, and R. J. Aitken, “Proteomic insights into the maturation and capacitation of mammalian spermatozoa,” Systems Biology in Reproductive Medicine, vol. 58, no. 4, pp. 211–217, 2012.
View at: Publisher Site | Google Scholar
R. Oliva, S. de Mateo, and J. M. Estanyol, “Sperm cell proteomics,” Proteomics, vol. 9, no. 4, pp. 1004–1017, 2009.
View at: Publisher Site | Google Scholar
Y. Gur and H. Breitbart, “Mammalian sperm translate nuclear-encoded proteins by mitochondrial-type ribosomes,” Genes & Development, vol. 20, no. 4, pp. 411–416, 2006.
View at: Publisher Site | Google Scholar
V. Torres-Flores, Y. L. Hernández-Rueda, P. D. Neri-Vidaurri et al., “Activation of protein kinase A stimulates the progesterone-induced calcium influx in human sperm exposed to the phosphodiesterase inhibitor papaverine,” Journal of Andrology, vol. 29, no. 5, pp. 549–557, 2008.
View at: Publisher Site | Google Scholar
V. Kumar, V. Kota, and S. Shivaji, “Hamster sperm capacitation: role of pyruvate dehydrogenase A and dihydrolipoamide dehydrogenase,” Biology of Reproduction, vol. 79, no. 2, pp. 190–199, 2008.
View at: Publisher Site | Google Scholar
H. Breitbart, G. Cohen, and S. Rubinstein, “Role of actin cytoskeleton in mammalian sperm capacitation and the acrosome reaction,” Reproduction, vol. 129, no. 3, pp. 263–268, 2005.
View at: Publisher Site | Google Scholar
C. L. R. Barratt and S. J. Publicover, “Sperm are promiscuous and CatSper is to blame...,” The EMBO Journal, vol. 31, no. 7, pp. 1624–1626, 2012.
View at: Publisher Site | Google Scholar
H. Qi, M. M. Moran, B. Navarro et al., “All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 4, pp. 1219–1223, 2007.
View at: Publisher Site | Google Scholar
P. V. Lishko, I. L. Botchkina, and Y. Kirichok, “Progesterone activates the principal Ca²⁺ channel of human sperm,” Nature, vol. 471, no. 7338, pp. 387–391, 2011.
View at: Publisher Site | Google Scholar
P. V. Lishko, I. L. Botchkina, A. Fedorenko, and Y. Kirichok, “Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel,” Cell, vol. 140, no. 3, pp. 327–337, 2010.
View at: Publisher Site | Google Scholar
B. Navarro, K. Miki, and D. E. Clapham, “ATP-activated P2X2 current in mouse spermatozoa,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 34, pp. 14342–14347, 2011.
View at: Publisher Site | Google Scholar
M. Gees, B. Colsoul, and B. Nilius, “The role of transient receptor potential cation channels in Ca²⁺ signaling,” Cold Spring Harbor Perspectives in Biology, vol. 2, no. 10, Article ID a003962, 2010.
View at: Publisher Site | Google Scholar
L. E. Castellano, C. L. Treviño, D. Rodríguez et al., “Transient receptor potential (TRPC) channels in human sperm: expression, cellular localization and involvement in the regulation of flagellar motility,” FEBS Letters, vol. 541, no. 1–3, pp. 69–74, 2003.
View at: Publisher Site | Google Scholar
M. Biel and S. Michalakis, “Cyclic nucleotide-gated channels,” Handbook of Experimental Pharmacology, vol. 191, pp. 111–136, 2009.
View at: Publisher Site | Google Scholar
B. Wiesner, J. Weiner, R. Middendorff, V. Hagen, U. B. Kaupp, and I. Weyand, “Cyclic nucleotide-gated channels on the flagellum control Ca²⁺ entry into sperm,” The Journal of Cell Biology, vol. 142, no. 2, pp. 473–484, 1998.
View at: Publisher Site | Google Scholar
M. Yoshida, M. Ishikawa, H. Izumi, R. de Santis, and M. Morisawa, “Store-operated calcium channel regulates the chemotactic behavior of ascidian sperm,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 1, pp. 149–154, 2003.
View at: Publisher Site | Google Scholar
G. Esposito, B. S. Jaiswal, F. Xie et al., “Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 2993–2998, 2004.
View at: Publisher Site | Google Scholar
K. C. Hess, B. H. Jones, B. Marquez et al., “The “soluble” adenylyl cyclase in sperm mediates multiple signaling events required for fertilization,” Developmental Cell, vol. 9, no. 2, pp. 249–259, 2005.
View at: Publisher Site | Google Scholar
K. Fukami, K. Nakao, T. Inoue et al., “Requirement of phospholipase Cδ4 for the zona pellucida-induced acrosome reaction,” Science, vol. 292, no. 5518, pp. 920–923, 2001.
View at: Publisher Site | Google Scholar
K. Fukami, M. Yoshida, T. Inoue et al., “Phospholipase Cδ4 is required for Ca²⁺ mobilization essential for acrosome reaction in sperm,” The Journal of Cell Biology, vol. 161, no. 1, pp. 79–88, 2003.
View at: Publisher Site | Google Scholar
G. Wennemuth, D. F. Babcock, and B. Hille, “Calcium clearance mechanisms of mouse sperm,” The Journal of General Physiology, vol. 122, no. 1, pp. 115–128, 2003.
View at: Publisher Site | Google Scholar
H. M. Florman, “Sequential focal and global elevations of sperm intracellular Ca²⁺ are initiated by the zona pellucida during acrosomal exocytosis,” Developmental Biology, vol. 165, no. 1, pp. 152–164, 1994.
View at: Publisher Site | Google Scholar
H. M. Florman, R. M. Tombes, N. L. First, and D. F. Babcock, “An adhesion-associated agonist from the zona pellucida activates G protein-promoted elevations of internal Ca²⁺ and pH that mediate mammalian sperm acrosomal exocytosis,” Developmental Biology, vol. 135, no. 1, pp. 133–146, 1989.
View at: Google Scholar
R. S. Tavares, S. Mansell, C. L. R. Barratt, S. M. Wilson, S. J. Publicover, and J. Ramalho-Santos, “ $p$ , $p^{′}$ -DDE activates CatSper and compromises human sperm function at environmentally relevant concentrations,” Human Reproduction, vol. 28, no. 12, pp. 3167–3177, 2013.
View at: Publisher Site | Google Scholar
J. Xia and D. Ren, “The BSA-induced Ca²⁺ influx during sperm capacitation is CATSPER channel-dependent,” Reproductive Biology and Endocrinology, vol. 7, article 119, 2009.
View at: Publisher Site | Google Scholar
J. L. Bailey and B. T. Storey, “Calcium influx into mouse spermatozoa activated by solubilized mouse zona pellucida, monitored with the calcium fluorescent indicator, fluo-3. Inhibition of the influx by three inhibitors of the zona pellucida induced acrosome reaction: tyrphostin A48, pertussis toxin, and 3-quinuclidinyl benzilate,” Molecular Reproduction and Development, vol. 39, no. 3, pp. 297–308, 1994.
View at: Publisher Site | Google Scholar
K. K. Shukla, W.-S. Kwon, M. S. Rahman, Y.-J. Park, Y.-A. You, and M.-G. Pang, “Nutlin-3a decreases male fertility via UQCRC2,” PLoS ONE, vol. 9, no. 8, Article ID e76959, 2013.
View at: Publisher Site | Google Scholar
R. Yanagimachi, “Mammalian fertilization,” in The Physiology of Reproduction, E. Knobil and J. D. Neill, Eds., pp. 189–317, Raven Press, New York, NY, USA, 1994.
View at: Google Scholar
C. R. Austin, “Observations on the penetration of the sperm in the mammalian egg,” Australian Journal of Scientific Research B: Biological Sciences, vol. 4, no. 4, pp. 581–596, 1951.
View at: Google Scholar
T. Strünker, N. Goodwin, C. Brenker et al., “The CatSper channel mediates progesterone-induced Ca²⁺ influx in human sperm,” Nature, vol. 471, no. 7338, pp. 382–386, 2011.
View at: Publisher Site | Google Scholar
A. Darszon, J. J. Acevedo, B. E. Galindo et al., “Sperm channel diversity and functional multiplicity,” Reproduction, vol. 131, no. 6, pp. 977–988, 2006.
View at: Publisher Site | Google Scholar
D. Pietrobon, F. di Virgilio, and T. Pozzan, “Structural and functional aspects of calcium homeostasis in eukaryotic cells,” European Journal of Biochemistry, vol. 193, no. 3, pp. 599–622, 1990.
View at: Google Scholar
Y. Kirichok, G. Krapivinsky, and D. E. Clapham, “The mitochondrial calcium uniporter is a highly selective ion channel,” Nature, vol. 427, no. 6972, pp. 360–364, 2004.
View at: Publisher Site | Google Scholar
J. Liu, J. Xia, K.-H. Cho, D. E. Clapham, and D. Ren, “CatSperβ, a novel transmembrane protein in the CatSper channel complex,” The Journal of Biological Chemistry, vol. 282, no. 26, pp. 18945–18952, 2007.
View at: Publisher Site | Google Scholar
H. Wang, J. Liu, K.-H. Cho, and D. Ren, “A novel, single, transmembrane protein CATSPERG is associated with CATSPER1 channel protein,” Biology of Reproduction, vol. 81, no. 3, pp. 539–544, 2009.
View at: Publisher Site | Google Scholar
D. Ren, B. Navarro, G. Perez et al., “A sperm ion channel required for sperm motility and male fertility,” Nature, vol. 413, no. 6856, pp. 603–609, 2001.
View at: Publisher Site | Google Scholar
D. Wang, S. M. King, T. A. Quill, L. K. Doolittle, and D. L. Garbers, “A new sperm-specific Na⁺/H⁺ exchanger required for sperm motility and fertility,” Nature Cell Biology, vol. 5, no. 12, pp. 1117–1122, 2003.
View at: Publisher Site | Google Scholar
A. E. Carlson, R. E. Westenbroek, T. Quill et al., “CatSper1 required for evoked Ca²⁺ entry and control of flagellar function in sperm,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 14864–14868, 2003.
View at: Publisher Site | Google Scholar
T. A. Quill, S. A. Sugden, K. L. Rossi, L. K. Doolittle, R. E. Hammer, and D. L. Garbers, “Hyperactivated sperm motility driven by CatSper2 is required for fertilization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 14869–14874, 2003.
View at: Publisher Site | Google Scholar
Y. Chen, M. J. Cann, T. N. Litvin et al., “Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor,” Science, vol. 289, no. 5479, pp. 625–628, 2000.
View at: Publisher Site | Google Scholar
D. E. Clapham, “Sperm BerserKers,” eLife, vol. 2, Article ID e01469, 2013.
View at: Publisher Site | Google Scholar
I. Weyand, M. Godde, S. Frings et al., “Cloning and functional expression of acyclic-nucleotide-gated channel from mammalian sperm,” Nature, vol. 368, no. 6474, pp. 859–863, 1994.
View at: Publisher Site | Google Scholar
S. S. Suarez and X. Dai, “Hyperactivation enhances mouse sperm capacity for penetrating viscoelastic media,” Biology of Reproduction, vol. 46, no. 4, pp. 686–691, 1992.
View at: Google Scholar
H.-C. Ho and S. S. Suarez, “Hyperactivation of mammalian spermatozoa: function and regulation,” Reproduction, vol. 122, no. 4, pp. 519–526, 2001.
View at: Google Scholar
M. Böhmer, Q. Van, I. Weyand et al., “Ca²⁺ spikes in the flagellum control chemotactic behavior of sperm,” The EMBO Journal, vol. 24, no. 15, pp. 2741–2752, 2005.
View at: Publisher Site | Google Scholar
B. Al-Anzi and D. E. Chandler, “A sperm chemoattractant is released from xenopus egg jelly during spawning,” Developmental Biology, vol. 198, no. 2, pp. 366–375, 1998.
View at: Publisher Site | Google Scholar
S. S. Suarez and A. A. Pacey, “Sperm transport in the female reproductive tract,” Human Reproduction Update, vol. 12, no. 1, pp. 23–37, 2006.
View at: Publisher Site | Google Scholar
S. S. Suarez, S. M. Varosi, and X. Dai, “Intracellular calcium increases with hyperactivation in intact, moving hamster sperm and oscillates with the flagellar beat cycle,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 10, pp. 4660–4664, 1993.
View at: Google Scholar
B. Marquez and S. S. Suarez, “Soluble adenylyl cyclase is required for activation of sperm but does not have a direct effect on hyperactivation,” Reproduction, Fertility and Development, vol. 20, no. 2, pp. 247–252, 2008.
View at: Publisher Site | Google Scholar
J. Xia, D. Reigada, C. H. Mitchell, and D. Ren, “CATSPER channel-mediated Ca²⁺ entry into mouse sperm triggers a tail-to-head propagation,” Biology of Reproduction, vol. 77, no. 3, pp. 551–559, 2007.
View at: Publisher Site | Google Scholar
P. E. Visconti, “Understanding the molecular basis of sperm capacitation through kinase design,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 3, pp. 667–668, 2009.
View at: Publisher Site | Google Scholar
P. E. Visconti, V. A. Westbrook, O. Chertihin, I. Demarco, S. Sleight, and A. B. Diekman, “Novel signaling pathways involved in sperm acquisition of fertilizing capacity,” Journal of Reproductive Immunology, vol. 53, no. 1-2, pp. 133–150, 2002.
View at: Publisher Site | Google Scholar
L. R. Fraser, “Sperm capacitation and the acrosome reaction,” Human Reproduction, vol. 13, no. 1, pp. 9–19, 1998.
View at: Publisher Site | Google Scholar
M. Michaut, C. N. Tomes, G. de Blas, R. Yunes, and L. S. Mayorga, “Calcium-triggered acrosomal exocytosis in human spermatozoa requires the coordinated activation of Rab3A and $N$ -ethylmaleimide-sensitive factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 18, pp. 9996–10001, 2000.
View at: Google Scholar
H. Breitbart, “Intracellular calcium regulation in sperm capacitation and acrosomal reaction,” Molecular and Cellular Endocrinology, vol. 187, no. 1-2, pp. 139–144, 2002.
View at: Publisher Site | Google Scholar
H. Breitbart, “Signaling pathways in sperm capacitation and acrosome reaction,” Cellular and Molecular Biology, vol. 49, no. 3, pp. 321–327, 2003.
View at: Google Scholar
H. Breitbart and Z. Naor, “Protein kinases in mammalian sperm capacitation and the acrosome reaction,” Reviews of Reproduction, vol. 4, no. 3, pp. 151–159, 1999.
View at: Publisher Site | Google Scholar
H. Breitbart and B. Spungin, “The biochemistry of the acrosome reaction,” Molecular Human Reproduction, vol. 3, no. 3, pp. 195–202, 1997.
View at: Google Scholar
H. M. Florman, M. K. Jungnickel, and K. A. Sutton, “Shedding Light on Sperm pHertility,” Cell, vol. 140, no. 3, pp. 310–312, 2010.
View at: Publisher Site | Google Scholar
N. Etkovitz, S. Rubinstein, L. Daniel, and H. Breitbart, “Role of PI3-kinase and PI4-kinase in actin polymerization during bovine sperm capacitation,” Biology of Reproduction, vol. 77, no. 2, pp. 263–273, 2007.
View at: Publisher Site | Google Scholar
P. E. Visconti and H. M. Florman, “Mechanisms of sperm-egg interactions: between sugars and broken bonds,” Science Signaling, vol. 3, no. 142, article pe35, 2010.
View at: Publisher Site | Google Scholar
A. Abou-haila and D. R. P. Tulsiani, “Signal transduction pathways that regulate sperm capacitation and the acrosome reaction,” Archives of Biochemistry and Biophysics, vol. 485, no. 1, pp. 72–81, 2009.
View at: Publisher Site | Google Scholar
R. K. Naz and P. B. Rajesh, “Role of tyrosine phosphorylation in sperm capacitation/acrosome reaction,” Reproductive Biology and Endocrinology, vol. 2, article 75, 2004.
View at: Publisher Site | Google Scholar
D. R. P. Tulsiani, A. Abou-Haila, C. R. Loeser, and B. M. J. Pereira, “The biological and functional significance of the sperm acrosome and acrosomal enzymes in mammalian fertilization,” Experimental Cell Research, vol. 240, no. 2, pp. 151–164, 1998.
View at: Publisher Site | Google Scholar
L. J. D. Zaneveld, C. J. de Jonge, R. A. Anderson, and S. R. Mack, “Human sperm capacitation and the acrosome reaction,” Human Reproduction, vol. 6, no. 9, pp. 1265–1274, 1991.
View at: Google Scholar
N. Bernabò, P. Berardinelli, A. Mauro et al., “The role of actin in capacitation-related signaling: an in silico and in vitro study,” BMC Systems Biology, vol. 5, article 47, 2011.
View at: Publisher Site | Google Scholar
C. Patrat, J. Auer, P. Fauque, R. L. Leandri, P. Jouannet, and C. Serres, “Zona pellucida from fertilised human oocytes induces a voltage-dependent calcium influx and the acrosome reaction in spermatozoa, but cannot be penetrated by sperm,” BMC Developmental Biology, vol. 6, article 59, 2006.
View at: Publisher Site | Google Scholar
R. A. Steinhardt, D. Epel, E. J. Carroli, and R. Yanagimachi, “Is calcium ionophore a universal activator for unfertilised eggs?” Nature, vol. 252, no. 5478, pp. 41–43, 1974.
View at: Google Scholar
M. Theodoridou, M. Nomikos, D. Parthimos et al., “Chimeras of sperm PLCζ reveal disparate protein domain functions in the generation of intracellular Ca²⁺ oscillations in mammalian eggs at fertilization,” Molecular Human Reproduction, vol. 19, no. 12, pp. 852–864, 2013.
View at: Publisher Site | Google Scholar
J. R. Gonzalez-Garcia, Z. Machaty, F. A. Lai, and K. Swann, “The dynamics of PKC-induced phosphorylation triggered by Ca²⁺ oscillations in mouse eggs,” Journal of Cellular Physiology, vol. 228, no. 1, pp. 110–119, 2013.
View at: Publisher Site | Google Scholar
M. J. Whitaker and R. A. Steinhardt, “Ionic regulation of egg activation,” Quarterly Reviews of Biophysics, vol. 15, no. 4, pp. 593–666, 1982.
View at: Google Scholar
L. F. Jaffe, “Sources of calcium in egg activation: a review and hypothesis,” Developmental Biology, vol. 99, no. 2, pp. 265–276, 1983.
View at: Google Scholar
S. Miyazaki, H. Shirakawa, K. Nakada, and Y. Honda, “Essential role of the inositol 1,4,5-trisphosphate receptor/Ca²⁺ release channel in Ca²⁺ waves and Ca²⁺ oscillations at fertilization of mammalian eggs,” Developmental Biology, vol. 158, no. 1, pp. 62–78, 1993.
View at: Publisher Site | Google Scholar
K. Swann and J.-P. Ozil, “Dynamics of the calcium signal that triggers mammalian egg activation,” International Review of Cytology, vol. 152, pp. 183–222, 1994.
View at: Google Scholar
K. Swann and F. A. Lai, “PLCζ and the initiation of Ca²⁺ oscillations in fertilizing mammalian eggs,” Cell Calcium, vol. 53, no. 1, pp. 55–62, 2013.
View at: Publisher Site | Google Scholar
A. Yu, M. Nomikos, M. Theodoridou, G. Nounesis, F. A. Lai, and K. Swann, “PLCζ causes Ca²⁺ oscillations in mouse eggs by targeting intracellular and not plasma membrane PI(4,5)P₂,” Molecular Biology of the Cell, vol. 23, no. 2, pp. 371–380, 2012.
View at: Publisher Site | Google Scholar
S. V. Phillips, Y. Yu, A. Rossbach et al., “Divergent effect of mammalian PLCζ in generating Ca²⁺ oscillations in somatic cells compared with eggs,” Biochemical Journal, vol. 438, no. 3, pp. 545–553, 2011.
View at: Publisher Site | Google Scholar
K. Swann and Y. Yu, “The dynamics of calcium oscillations that activate mammalian eggs,” The International Journal of Developmental Biology, vol. 52, no. 5-6, pp. 585–594, 2008.
View at: Publisher Site | Google Scholar
B.-G. Jeon, J.-S. Moon, K.-C. Kim, H.-J. Lee, S.-Y. Choe, and G.-J. Rho, “Follicular fluid enhances sperm attraction and its motility in human,” Journal of Assisted Reproduction and Genetics, vol. 18, no. 8, pp. 407–412, 2001.
View at: Publisher Site | Google Scholar
H.-C. Ho, K. A. Granish, and S. S. Suarez, “Hyperactivated motility of bull sperm is triggered at the axoneme by Ca²⁺ and not cAMP,” Developmental Biology, vol. 250, no. 1, pp. 208–217, 2002.
View at: Publisher Site | Google Scholar
M. Luconi, G. Forti, and E. Baldi, “Pathophysiology of sperm motility,” Frontiers in Bioscience, vol. 11, no. 2, pp. 1433–1447, 2006.
View at: Google Scholar
A. Revelli, D. Ghigo, F. Moffa, M. Massobrio, and I. Tur-Kaspa, “Guanylate cyclase activity and sperm function,” Endocrine Reviews, vol. 23, no. 4, pp. 484–494, 2002.
View at: Publisher Site | Google Scholar
K. Taskén and E. M. Aandahl, “Localized effects of cAMP mediated by distinct routes of protein kinase A,” Physiological Reviews, vol. 84, no. 1, pp. 137–167, 2004.
View at: Publisher Site | Google Scholar
K. Swann, “Soluble sperm factors and Ca²⁺ release in eggs at fertilization,” Reviews of Reproduction, vol. 1, no. 1, pp. 33–39, 1996.
View at: Google Scholar
K. Swann, M. G. Larman, C. M. Saunders, and F. A. Lai, “The cytosolic sperm factor that triggers Ca²⁺ oscillations and egg activation in mammals is a novel phospholipase C: PLCζ,” Reproduction, vol. 127, no. 4, pp. 431–439, 2004.
View at: Google Scholar

Copyright

Copyright © 2014 Md Saidur Rahman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

10000

Downloads

2955

Citations

BioMed Research International

New Advances in Reproductive Biomedicine

Calcium Influx and Male Fertility in the Context of the Sperm Proteome: An Update

Abstract

1. Introduction

2. Mechanism of Ca2+ Influx in Mammalian Spermatozoa

3. Effect of Ca2+ Influx on Male Fertility

3.1. Ca2+ Influx, Sperm Hyperactivation, Chemotaxis, and Protein Functions

3.2. Ca2+ Influx versus Capacitation, the Acrosomal Reaction, Fertilization, and Sperm Proteome

3.3. Ca2+ Influx and Postfertilization Egg Activation in Context of Sperm Proteome

4. Future Prospects

Conflict of Interests

Acknowledgments

References

Copyright

2. Mechanism of Ca²⁺ Influx in Mammalian Spermatozoa

3. Effect of Ca²⁺ Influx on Male Fertility

3.1. Ca²⁺ Influx, Sperm Hyperactivation, Chemotaxis, and Protein Functions

3.2. Ca²⁺ Influx versus Capacitation, the Acrosomal Reaction, Fertilization, and Sperm Proteome

3.3. Ca²⁺ Influx and Postfertilization Egg Activation in Context of Sperm Proteome