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Progesterone's role in sperm The female steroid hormone progesterone is produced by the ovaries and the placenta, and supports gestation and embryogenesis through its actions on a well-characterized nuclear progesterone receptor. But progesterone released by cells surrounding the egg also stimulates sperm cells within the Fallopian tubes and increases their fertilizing ability, and the mechanism of this action of progesterone has remained elusive. Two independent research groups now report that progesterone potently activates CatSper, the principal Ca 2+ channel of the sperm flagellum. Their data demonstrate that the CatSper channel or a directly associated membrane protein serves as a novel progesterone receptor that can mediate a fast, non-genomic effect of progesterone at the level of the sperm plasma membrane. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Progesterone stimulates an increase in Ca 2+ levels in human sperm, but the underlying signalling mechanism is poorly understood. Two studies now show that progesterone activates the sperm-specific, pH-sensitive CatSper calcium channel, leading to a rapid influx of Ca 2+ ions into the spermatozoa. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg’s protective vestments 1 . Progesterone induces Ca 2+ influx into spermatozoa 1 , 2 , 3 and triggers multiple Ca 2+ -dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg 4 , 5 , 6 , 7 , 8 . As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor 9 . However, the effect of progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane progesterone receptor 5 , 10 . The identity of this non-genomic progesterone receptor and the mechanism by which it causes Ca 2+ entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of progesterone on human spermatozoa by identifying the Ca 2+ channel activated by progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of progesterone dramatically potentiate CatSper, a pH-dependent Ca 2+ channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic progesterone receptor of sperm. Given that the CatSper-associated progesterone receptor is sperm specific and structurally different from the genomic progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.

The flagella of mammalian sperm display non-planar, asymmetric beating, in contrast to the planar, symmetric beating of flagella from sea urchin sperm and unicellular organisms. The molecular basis of this difference is unclear. Here, we perform in situ cryo-electron tomography of mouse and human sperm, providing the highest-resolution structural information to date. Our subtomogram averages reveal mammalian sperm-specific protein complexes within the microtubules, the radial spokes and nexin–dynein regulatory complexes. The locations and structures of these complexes suggest potential roles in enhancing the mechanical strength of mammalian sperm axonemes and regulating dynein-based axonemal bending. Intriguingly, we find that each of the nine outer microtubule doublets is decorated with a distinct combination of sperm-specific complexes. We propose that this asymmetric distribution of proteins differentially regulates the sliding of each microtubule doublet and may underlie the asymmetric beating of mammalian sperm. The flagella of mammalian sperm display non-planar, asymmetric beating, but the molecular basis is unclear. Chen et al. performed in situ cryo-ET of mouse and human sperm and discovered asymmetric distributions of regulatory complexes that could generate asymmetric bending force.

Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme α/β hydrolase domain–containng protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization.

Ion channels control the ability of human sperm to fertilize the egg by triggering hyperactivated motility, which is regulated by membrane potential, intracellular pH, and cytosolic calcium. Previous studies unraveled three essential ion channels that regulate these parameters: (1) the Ca2+ channel CatSper, (2) the K+ channel KSper, and (3) the H+ channel Hv1. However, the molecular identity of the sperm Na+ conductance that mediates initial membrane depolarization and, thus, triggers downstream signaling events is yet to be defined. Here, we functionally characterize DSper, the Depolarizing Channel of Sperm, as the temperature-activated channel TRPV4. It is functionally expressed at both mRNA and protein levels, while other temperature-sensitive TRPV channels are not functional in human sperm. DSper currents are activated by warm temperatures and mediate cation conductance, that shares a pharmacological profile reminiscent of TRPV4. Together, these results suggest that TRPV4 activation triggers initial membrane depolarization, facilitating both CatSper and Hv1 gating and, consequently, sperm hyperactivation.

The female steroid hormone progesterone regulates ovulation and supports pregnancy, but also controls human sperm function within the female reproductive tract. Progesterone causes elevation of sperm intracellular Ca²⁺ leading to sperm hyperactivation, acrosome reaction, and perhaps chemotaxis toward the egg. Although it has been suggested that progesterone-dependent Ca²⁺ influx into human spermatozoa is primarily mediated by cationic channel of sperm (CatSper), the principal flagellar Ca²⁺ channel of sperm, conclusive loss-of-function genetic evidence for activation of CatSper by progesterone has yet to be provided. Moreover, it is not clear whether the responsiveness of CatSper to progesterone is an innate property of human spermatozoa or is acquired as the result of exposure to the seminal plasma. Here, by recording ionic currents from spermatozoa of an infertile CatSper-deficient patient, we demonstrate that CatSper is indeed the principal Ca²⁺ channel of human spermatozoa, and that it is strongly potentiated by progesterone. In addition, by recording CatSper currents from human epididymal and testicular spermatozoa, we show that CatSper sensitivity to progesterone arises early in sperm development and increases gradually to a peak when spermatozoa are ejaculated. These results unambiguously establish an important role of CatSper channel in human sperm nongenomic progesterone signaling and demonstrate that the molecular mechanism responsible for activation of CatSper by progesterone arises early in sperm development concurrently with the CatSper channel itself.

The flagellar calcium channel CatSper is essential for male fertility, as it regulates calcium influx to trigger the hyperactive motility required for sperm to fertilize the egg. Precise activation of CatSper is critical, as premature activation can impair sperm function. While optimal temperature is known to influence fertilization, its effect on CatSper remains unknown. By directly recording from mouse spermatozoa, we reveal that CatSper functions as a temperature-gated ion channel, with a thermal threshold of 33.5 °C and a temperature coefficient Q 10 of 5.1. Additionally, we show that physiological levels of spermine reversibly inhibit CatSper’s temperature gating, protecting against premature activation. Our findings highlight for the first time the presence of the temperature-gating modality of CatSper and reveal the protective role of spermine, a major component of seminal plasma. These results emphasize the need to maintain testes below 34 °C for optimal fertility and advance understanding of CatSper regulation in male fertility. Here they show that the essential sperm calcium channel CatSper is temperature-gated and reversibly inhibited by spermine. This discovery uncovers a key regulatory mechanism of sperm function and highlights the critical role of testicular cooling in male fertility.

The sperm calcium channel CatSper plays a central role in successful fertilization as a primary Ca 2+ gateway. Here, we applied cryo-electron tomography to visualize the higher-order organization of the native CatSper complex in intact mammalian sperm. The repeating CatSper units form long zigzag-rows along mouse and human sperm flagella. Above each tetrameric channel pore, most of the extracellular domains form a canopy that interconnects to a zigzag-shaped roof. Murine CatSper contains an additional wing-structure connected to the tetrameric channel. The intracellular domains link two neighboring channels to a diagonal array, suggesting a dimer formation. Fitting of an atomic model of isolated monomeric CatSper to the in situ map reveals supramolecular interactions and assembly of the CatSper complex. Loss of EFCAB9-CATSPERζ alters the architecture and interactions of the channels, resulting in fragmentation and misalignment of the zigzag-rows and disruption of flagellar movement in Efcab9 −/− sperm. This work offers unique insights into the structural basis for understanding CatSper regulation of sperm motility. Sperm motility and male fertility requires function of the CatSper calcium channels. Here, using cryo-electron tomography, authors visualize the native in-cell 3D structure and higher-order organization of the CatSper as long zigzag rows along the sperm tail.

A growing number of studies point to reduced fertility upon chronic exposure to endocrine-disrupting chemicals (EDCs) such as phthalates and plasticizers. These toxins are ubiquitous and are often found in food and beverage containers, medical devices, as well as in common household and personal care items. Animal studies with EDCs, such as phthalates and bisphenol A have shown a dose-dependent decrease in fertility and embryo toxicity upon chronic exposure. However, limited research has been conducted on the acute effects of these EDCs on male fertility. Here we used a murine model to test the acute effects of four ubiquitous environmental toxins: bisphenol A (BPA), di-2-ethylhexyl phthalate (DEHP), diethyl phthalate (DEP), and dimethyl phthalate (DMP) on sperm fertilizing ability and pre-implantation embryo development. The most potent of these toxins, di-2-ethylhexyl phthalate (DEHP), was further evaluated for its effect on sperm ion channel activity, capacitation status, acrosome reaction and generation of reactive oxygen species (ROS). DEHP demonstrated a profound hazardous effect on sperm fertility by producing an altered capacitation profile, impairing the acrosome reaction, and, interestingly, also increasing ROS production. These results indicate that in addition to its known chronic impact on reproductive potential, DEHP also imposes acute and profound damage to spermatozoa, and thus, represents a significant risk to male fertility.

Mammalian spermatozoa gain competence to fertilize an oocyte as they travel through the female reproductive tract. This process is accompanied by an elevation of sperm intracellular calcium and a membrane hyperpolarization. The latter is evoked by K+ efflux; however, the molecular identity of the potassium channel of human spermatozoa (hKSper) is unknown. Here, we characterize hKSper, reporting that it is regulated by intracellular calcium but is insensitive to intracellular alkalinization. We also show that human KSper is inhibited by charybdotoxin, iberiotoxin, and paxilline, while mouse KSper is insensitive to these compounds. Such unique properties suggest that the Slo1 ion channel is the molecular determinant for hKSper. We show that Slo1 is localized to the sperm flagellum and is inhibited by progesterone. Inhibition of hKSper by progesterone may depolarize the spermatozoon to open the calcium channel CatSper, thus raising [Ca2+] to produce hyperactivation and allowing sperm to fertilize an oocyte. The sperm cells that are released into the female reproductive tract when a mammal ejaculates, are not capable of fertilizing an egg right away, so they must go through a process called maturation. The early stages of this process involve interactions with the seminal fluid that increase the motility of the sperm cells, and the latter stages involve interactions with the walls of the reproductive tract and vaginal secretions to ensure that the sperm cells move toward the egg. Many of these interactions involve positive ions entering and leaving the sperm cells via ion channels. The properties of the ion channels that allow protons and calcium ions to move into and out of human sperm cells are well understood, but little is known about the channels that control the movement of the potassium (K) ions. At first it was assumed that the molecular structure of these channels was similar to that of the Slo3 potassium channel in mouse sperm, but crucial differences between human and mouse sperm cells have been reported in recent years. Now Mannowetz et al. have shown that the potassium channel in human sperm is opened by increased levels of calcium ions inside the sperm cells. Moreover, the pH inside the sperm cells had no influence on this process. Furthermore, the channel was blocked by three toxins that have no effect on the Slo3 potassium channels in mice, but are known to block a type of potassium channel known as Slo1. Mannowetz et al. then used a technique called Western blotting to confirm the presence of Slo1 potassium channels in the tails of human sperm cells. Mannowetz et al. also showed that the Slo1 potassium channel can be blocked by the female hormone progesterone. This is important because blocking the potassium channels causes the calcium ion channels in the cells to open fully, and the resulting influx of calcium ions triggers a process called sperm hyperactivation that makes it possible for the sperm cell to fertilize the egg. By clearly showing the fundamental differences between human sperm cells and mouse sperm cells, this work stresses the need to exercise caution in using mice as a model of male fertility in humans.

The calcium channel of sperm (CatSper) is essential for sperm hyperactivated motility and fertility. The steroid hormone progesterone activates CatSper of human sperm via binding to the serine hydrolase ABHD2. However, steroid specificity of ABHD2 has not been evaluated. Here, we explored whether steroid hormones to which human spermatozoa are exposed in the male and female genital tract influence CatSper activation via modulation of ABHD2. The results show that testosterone, estrogen, and hydrocortisone did not alter basal CatSper currents, whereas the neurosteroid pregnenolone sulfate exerted similar effects as progesterone, likely binding to the same site. However, physiological concentrations of testosterone and hydrocortisone inhibited CatSper activation by progesterone. Additionally, testosterone antagonized the effect of pregnenolone sulfate. We have also explored whether steroid-like molecules, such as the plant triterpenoids pristimerin and lupeol, affect sperm fertility. Interestingly, both compounds competed with progesterone and pregnenolone sulfate and significantly reduced CatSper activation by either steroid. Furthermore, pristimerin and lupeol considerably diminished hyperactivation of capacitated spermatozoa. These results indicate that (i) pregnenolone sulfate together with progesterone are the main steroids that activate CatSper and (ii) pristimerin and lupeol can act as contraceptive compounds by averting sperm hyperactivation, thus preventing fertilization.