Importance of SLC26 Transmembrane Anion Exchangers in Sperm Post-testicular Maturation and Fertilization Potential

Abstract

In mammals, sperm cells produced within the testis are structurally differentiated but remain immotile and are unable to fertilize the oocyte unless they undergo a series of maturation events during their transit in the male and female genital tracts. This post-testicular functional maturation is known to rely on the micro-environment of both male and female genital tracts, and is tightly controlled by the pH of their luminal milieus. In particular, within the epididymis, the establishment of a low bicarbonate (HCO3–) concentration contributes to luminal acidification, which is necessary for sperm maturation and subsequent storage in a quiescent state. Following ejaculation, sperm is exposed to the basic pH of the female genital tract and bicarbonate (HCO3–), calcium (Ca2+), and chloride (Cl–) influxes induce biochemical and electrophysiological changes to the sperm cells (cytoplasmic alkalinization, increased cAMP concentration, and protein phosphorylation cascades), which are indispensable for the acquisition of fertilization potential, a process called capacitation. Solute carrier 26 (SLC26) members are conserved membranous proteins that mediate the transport of various anions across the plasma membrane of epithelial cells and constitute important regulators of pH and HCO3– concentration. Most SLC26 members were shown to physically interact and cooperate with the cystic fibrosis transmembrane conductance regulator channel (CFTR) in various epithelia, mainly by stimulating its Cl– channel activity. Among SLC26 members, the function of SLC26A3, A6, and A8 were particularly investigated in the male genital tract and the sperm cells. In this review, we will focus on SLC26s contributions to ionic- and pH-dependent processes during sperm post-testicular maturation. We will specify the current knowledge regarding their functions, based on data from the literature generated by means of in vitro and in vivo studies in knock-out mouse models together with genetic studies of infertile patients. We will also discuss the limits of those studies, the current research gaps and identify some key points for potential developments in this field.

The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility

“…The first and most remarkable evidence was provided for the CATSPER channel, for which mutations ( CATSPER 1–2‐ε subunits) were identified in several asthenoteratozoospermic individuals with altered fertilizing capacity and/or sperm with coiled flagella 12,39 . More recently, pathogenic variants affecting members of the SLC26 family of anion exchangers, namely SLC26A3 and SLC26A8 ( TAT1 ), were also shown to impair the functionality of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, causing asthenozoospermia, associated with defective capacitation, midpiece and annulus disorganization in the case of SLC26A8 11,40,41 . The voltage‐dependent anion channels VDAC2 and 3 were also identified with pathogenic defects leading to idiopathic asthenozoospermia 9,42 .…”

“…1, 7,8 Importantly, asthenozoospermia is also detected in the complete absence of morphological defects, suggesting the involvement of functional defects in activation and/or regulation of flagellar beating. To date, such cases of functional asthenozoospermia remain poorly characterized, and only a few mutations were identified in genes encoding for proteins with enzymatic properties ( GALNTL5 ), seminal components ( SEMG1 ) and ion channels ( CATSPER1‐2‐ε , SLC26A3 , VDAC2 ) 1,9‐12 . Overall, the knowledge obtained by studying those sperm pathological phenotypes provides evidence that, in addition to proper morphology and structure, sperm fertilization potential relies on proper activation of the signalling pathways regulating motility, metabolism and energy production.…”

Signaling Enzymes Required for Sperm Maturation and Fertilization in Mammals

“…More recently, elevation of pHi has also been recognized to be a key event required for initiation of calcium influx during sperm hyperactivation. Knockout of channels, Slo3, NHE1 (Slca9c) or SLC26A3, responsible for changes in pH renders sperm infertile (Wang et al, 2007;Chen et al, 2009;Santi et al, 2010;Zeng et al, 2011;Chavez et al, 2014;Toure, 2019). A significant advance in understanding hyperactivation came from the discovery of calcium channels (CatSper) as essential mediators of sperm calcium influx.…”

Network Analyses Predict Small RNAs That Might Modulate Gene Expression in the Testis and Epididymis of Bos indicus Bulls

“…The cystic fibrosis transmembrane conductance regulator (CFTR) gene was up-regulated in the head epididymis when compared to the testis. The CFTR channel is involved in sperm capacitation (Touré, 2019) and can contribute to the Cl − and bicarbonate fluxes (Touré, 2019). The DE gene SLC26A3, upregulated in the epididymis, is essential to bicarbonate fluxes and interacts with the CFTR channel (Touré, 2019).…”