CatSper Research Articles

Evolutionary Genomics Reveals Lineage-Specific Gene Loss and Rapid Evolution of a Sperm-Specific Ion Channel Complex: CatSpers and CatSperβ

The mammalian CatSper ion channel family consists of four sperm-specific voltage-gated Ca2+ channels that are crucial for sperm hyperactivation and male fertility. All four CatSper subunits are believed to assemble into a heteromultimeric channel complex, together with an auxiliary subunit, CatSperβ. Here, we report a comprehensive comparative genomics study and evolutionary analysis of CatSpers and CatSperβ, with important correlation to physiological significance of molecular evolution of the CatSper channel complex. The development of the CatSper channel complex with four CatSpers and CatSperβ originated as early as primitive metazoans such as the Cnidarian Nematostella vectensis. Comparative genomics revealed extensive lineage-specific gene loss of all four CatSpers and CatSperβ through metazoan evolution, especially in vertebrates. The CatSper channel complex underwent rapid evolution and functional divergence, while distinct evolutionary constraints appear to have acted on different domains and specific sites of the four CatSper genes. These results reveal unique evolutionary characteristics of sperm-specific Ca2+ channels and their adaptation to sperm biology through metazoan evolution.

CatSper genes expression, semen characteristics and histology of testes in the contusive spinal cord-injured mice model

Experimental study. A recently characterized CatSper genes, encodes for unique Ca(2+) channels in the testes, where they play essential roles in sperm motility. The aim of this research is to evaluate potential changes in the expression of CatSper genes, sperm parameters and testis histology following spinal cord injury (SCI). Department of Anatomical Sciences, Tarbiat Modares University, Tehran, Iran. A total of 75 adult NMRI mice were divided into three groups (25 in each group) of SCI, sham and control. Following laminectomy, SCI group was subjected to injury at the ninth thoracic vertebra. The epididymal sperm parameters were studied at day 1 and at weeks 1, 2, 4 and 6 after injury. One testis was removed for morphological study and the other testis were used for molecular study. Reverse transcription-PCR was performed at different time in all the groups. Our results revealed that SCI affects spermatogenesis as well as sperm quality and quantity. In gene expression analysis, there was a significant downregulation of CatSpers 1 and 2 at 4 and 6 weeks following contusion. There were no differences between the semen parameters and CatSper genes expression at the different time points in the sham and control groups. Our data indicated that the SCI mouse model causes a significant reduction in all sperm parameters, along with deleterious effects on spermatogenesis as well as the expression of CatSpers 1 and 2.

Catsper3 and Catsper4 Are Essential for Sperm Hyperactivated Motility and Male Fertility in the Mouse1

Catsper3 and Catsper4 are two recently identified testis-specific genes homologous to Catsper1 and Catsper2 that have been shown to play an essential role in sperm hyperactivated motility and male fertility in mice. Here we report that Catsper3 and Catsper4 knockout male mice are completely infertile due to a quick loss of motility and a lack of hyperactivated motility under capacitating conditions. Our data demonstrate that both CATSPER3 and CATSPER4 are required for hyperactivated sperm motility during capacitation and for male fertility. The present study also demands a revisit to the idiopathic male infertility patients who show normal sperm counts and normal initial motility for defects in sperm hyperactivated motility and for potential CATSPER gene mutations. The CATSPER channel also may be an excellent drug target for male contraceptives.

Voltage-dependent calcium channels in mammalian spermatozoa revisited

The last few years have seen an explosion in the number of voltage-dependent ion channel sequences detected in sperm and testes. The complex structural paradigm of these channels is now known to include a pore-forming alpha1 subunit(s) whose electrophysiological properties are modulated by an intracellular beta subunit, a disulfide-linked complex of a membrane-spanning delta subunit with an extracellular alpha2 subunit, and a transmembrane gamma subunit. Many of these are alternatively spliced. Furthermore, the known number of genes coding each subtype has expanded significantly (10 alpha1, 4 beta, 4 alpha2delta, 8 gamma). Recently, the CatSper gene family has been characterized based on similarity to the voltage-dependent calcium channel alpha1 subunit. From among this multiplicity, a wide cross-section is active in sperm, including many splice variants. For example, expression of the various alpha1 subunits appears strictly localized in discrete domains of mature sperm, and seems to control distinct physiological roles such as cellular signaling pathways. These include alpha1 alternative splicing variants that are regulated by ions passed by channels in developing sperm. Various combinations of ion channel sequence variants have been studies in research models and in a variety of human diseases, including male infertility. For example, rats that are genetically resistant to testes damage by lead seem to respond to lead ions by increasing alpha1 alternative splicing. In contrast, in varicocele-associated male infertility, the outcome from surgical correction correlates with suppression of alpha1 alternative splicing, Ion channel blockers remain attractive model contraceptive drugs because of their ability to modulate cholesterol levels. However, the large number of sperm ion channel variants shared with other cell types make ion channels less attractive targets for male contraceptive development than a few years ago. In this review, the genetics, structure and function of voltage-dependent calcium channels and related CatSper molecules will be discussed, and several practical clinical applications associated with these channels will be reported.

Insights into sperm cell motility signaling through sNHE and the CatSpers

Successful natural reproduction normally requires vigorously motile spermatozoa. Using a signal peptide trapping strategy, we identified two new genes, a putative sperm Na +/H + exchanger (sNHE) and the putative cation channel CatSper2, with unique and essential roles in sperm motility. Disruption of the sNHE or CatSper2 genes in mice caused male infertility due to immotile spermatozoa or failed motility hyperactivation, respectively, without other apparent abnormalities. The immotility phenotype of the sNHE null spermatozoa appears to result from an intimate association of sNHE and the atypical adenylyl cyclase (sAC), while a failure of calcium entry requiring an apparent CatSper1 and -2 heteromeric ion channel correlates with a hyperactivation defect in these null animals. The specific expression of sNHE and the CatSpers in spermatozoa and their required function in cell motility make them excellent potential targets for the development of novel male contraceptives.

Sperm Ion Channels: Molecular Targets for the Next Generation of Contraceptive Medicines?

Sperm Ion Channels: Molecular Targets for the Next Generation of Contraceptive Medicines?

CatSper gene expression in postnatal development of mouse testis and in subfertile men with deficient sperm motility.

The search for Ca2+ channels residing in sperm has led to the recent cloning and characterization of a novel gene, named CatSper, which codes for a unique Ca2+ channel expressed exclusively in the testis. It plays an essential role in sperm motility, penetration into the oocyte, and ultimately in male fertility. In this study, we assessed the temporal profile of CatSper gene expression during mouse testis development and performed a semi-quantitative evaluation of expression levels in a group of subfertile men which lack sperm motility. A small piece of testicular tissue obtained by either multi-site testicular biopsy or orchidectomy was used for semi-quantitative RT-PCR of CatSper and beta2-microglobulin (beta2m, as an internal control) genes. Our results reveal that: (i) the expression of mouse CatSper is developmentally regulated with a direct correlation between CatSper expression and mouse sexual maturation. CatSper gene expression is first detected at 3 weeks of age and coincides with the appearance of round spermatids in the developing mouse testis. (ii) There is a significant reduction in the level of CatSper gene expression (up to 3.5-fold difference) among patients which lack sperm motility as compared with patients whose infertility cannot be ascribed to a deficiency in motility (used as a control). The data obtained in this study support a potential role for CatSper in sperm motility and fertility in mouse and human. CatSper is therefore implicated as a potential target to explore the molecular mechanisms of male infertility.