Estrogenic regulation of bicarbonate transporters from SLC4 family in rat Sertoli cells (original) (raw)
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Molecular Basis of Bicarbonate Membrane Transport in the Male Reproductive Tract
Current Medicinal Chemistry, 2013
Bicarbonate (HCO 3 -) membrane transport systems are crucial players in the physiology of several tissues. The molecular basis of HCO 3 membrane transport is of major physiological relevance since this ion is involved in the establishment of intracellular and extracellular ionic composition, osmolariy and pH. The membrane HCO 3 transporters are divided in two main families: solute carrier 4 (SLC4) and solute carrier 26 (SLC26), although HCO 3 concentration can also be regulated by the cystic fibrosis transmembrane regulator (CFTR). In most tissues the SLC4 family represents the majority of HCO 3 transporters members, which can be divided in two subgroups: the Na + -dependent and the Na +independent transporters. The SLC26 family consists of ten members that can transport diverse ions besides HCO 3 -.
Control of intracellular pH and bicarbonate by CO2 diffusion into human sperm
Nature Communications
The reaction of CO2 with H2O to form bicarbonate (HCO3−) and H+ controls sperm motility and fertilization via HCO3−-stimulated cAMP synthesis. A complex network of signaling proteins participates in this reaction. Here, we identify key players that regulate intracellular pH (pHi) and HCO3− in human sperm by quantitative mass spectrometry (MS) and kinetic patch-clamp fluorometry. The resting pHi is set by amiloride-sensitive Na+/H+ exchange. The sperm-specific putative Na+/H+ exchanger SLC9C1, unlike its sea urchin homologue, is not gated by voltage or cAMP. Transporters and channels implied in HCO3− transport are not detected, and may be present at copy numbers < 10 molecules/sperm cell. Instead, HCO3− is produced by diffusion of CO2 into cells and readjustment of the CO2/HCO3−/H+ equilibrium. The proton channel Hv1 may serve as a unidirectional valve that blunts the acidification ensuing from HCO3− synthesis. This work provides a new framework for the study of male infertility.
Proceedings of the National Academy of Sciences, 2001
Estrogen receptor ␣ (ER␣) is essential for male fertility. Its activity is responsible for maintaining epithelial cytoarchitecture in efferent ductules and the reabsorption of fluid for concentrating sperm in the head of the epididymis. These discoveries and others have helped to establish estrogen's bisexual role in reproductive importance. Reported here is the molecular mechanism to explain estrogen's role in fluid reabsorption in the male reproductive tract. It is shown that estrogen regulates expression of the Na ؉ ͞H ؉ exchanger-3 (NHE3) and the rate of 22 Na ؉ transport, sensitive to an NHE3 inhibitor. Immunohistochemical staining for NHE3, carbonic anhydrase II (CAII), and aquaporin-I (AQP1) was decreased in ER␣ knockout (␣ERKO) efferent ductules. Targeted gene-deficient mice were compared with ␣ERKO, and the NHE3 knockout and CAIIdeficient mice showed ␣ERKO-like fluid accumulation, but only the NHE3 knockout and ␣ERKO mice were infertile. Northern blot analysis showed decreases in mRNA for NHE3 in ␣ERKO and antiestrogen-treated mice. The changes in AQP1 and CAII in ␣ERKO seemed to be secondary because of the disruption of apical cytoarchitecture. Ductal epithelial ultrastructure was abnormal only in ␣ERKO mice. Thus, in the male, estrogen regulates one of the most important epithelial ion transporters and maintains epithelial morphological differentiation in efferent ductules of the male, independent of its regulation of Na ؉ transport. Finally, these data raise the possibility of targeting ER␣ in developing a contraceptive for the male.
Physiology of na+/h+ exchangers in the male reproductive tract: relevance for male fertility
Biology of reproduction, 2014
The maintenance of pH homeostasis in the male reproductive tract is kept through the involvement of several mechanisms, among which is included the transmembranous movement of H(+) ions. Na(+)-H(+) exchangers (SLC9, solute carrier 9 family members) are among the membrane transporters known to participate in intracellular and extracellular pH regulation but also have important roles in salt and water absorption across epithelia and in the regulation of cell volume. The presence of several Na(+)-H(+) exchangers has been reported in the male reproductive tract. Their involvement in the processes that ensure the correct pursuance of the spermatogenetic event and spermatozoa maturation has been suggested. Indeed, the formation of mature spermatozoa is highly dependent on the maintenance of adequate ductal luminal milieu pH and ionic balance. Perturbations in these processes result in reduced male reproductive potential and consequently male subfertility and/or infertility. Thus, it is im...
Effect of Prediabetes on Membrane Bicarbonate Transporters in Testis and Epididymis
The Journal of Membrane Biology, 2013
The formation of competent spermatozoa is a complex event that depends on the establishment of adequate environments throughout the male reproductive tract. This includes the control of bicarbonate (HCO 3 -) concentration, which plays an essential role in the maintenance of extracellular and intracellular pH (pH i ) values. Diabetes mellitus alters pH i regulation in mammalian cells, mainly by altering the activity of ion transporters, particularly HCO 3 --dependent mechanisms. Yet, little is known about the effects of this pathology and its prodromal stage, prediabetes, on the membrane transport mechanisms of male reproductive tract cells. Herein, we analyzed protein and mRNA levels of the most relevant HCO 3 transporters of the SLC4 family [anion exchanger 2 (AE2), Na ? -driven Cl -/HCO 3 exchanger (NDCBE), electrogenic Na ? / HCO 3 cotransporter 1 (NBCe1), electroneutral Na ? / HCO 3 cotransporter 1 (NBCn1)] in the testis and epididymis of a prediabetic animal model. Firstly, we identified the HCO 3 transporters of the SLC4 family, in both testicular and epididymal tissue. Secondly, although no alterations were detected in protein expression, mRNA levels of NBCe1, NBCn1 and NDCBE were significantly increased in the testis of prediabetic rats. On the other hand, in the epididymis, prediabetes caused an increase of AE2 and a decrease of NDCBE protein levels. These alterations may be translated into changes of HCO 3
Anion exchanger 2 is essential for spermiogenesis in mice
Proceedings of the National Academy of Sciences, 2003
Na ؉ -independent anion exchangers (AE) mediate electroneutral exchange of Cl ؊ for HCO 3 ؊ ions across cell membranes, being involved in intracellular pH and cell volume regulation and in transepithelial hydroionic fluxes. Bicarbonate activation of adenylyl cyclase is known to be necessary for sperm motility and sperm capacitation, and a few studies have suggested a possible role of AE carriers in reproduction. Among the four AE genes identified in mammals thus far, only Ae2 (Slc4a2) has been determined to be expressed in the male reproductive system, especially in developing spermatozoa and in epididymal epithelium. Most AE genes drive alternative transcription, which in mouse Ae2 results in several Ae2 isoforms. Here, we generated mice carrying a targeted disruption of Ae2 that prevents the expression of the three AE2 isoforms (Ae2a, Ae2b1, and Ae2b2) normally found in mouse testes. Male Ae2 ؊/؊ mice (but not female Ae2 ؊/؊ mice) are infertile.
Role of the Na+/Ca2+ exchanger in calcium homeostasis and human sperm motility regulation
Cell Motility and the Cytoskeleton, 2006
A number of cell functions, such as flagellar beating, swimming velocity, acrosome reaction, etc., are triggered by a Ca 2þ influx across the cell membrane. For appropriate physiological functions, the motile human sperm maintains the intracellular free calcium concentration ([Ca 2þ ] i ) at a submicromolar level. The objective of this study was to determine the role of the Na þ /Ca 2þ exchanger (NCX) in the maintenance of [Ca 2þ ] i in human spermatozoa. Spermatozoa maintained in extracellular medium containing !1 lM Ca 2þ exhibited motility similar to that of the control. In addition to several calcium transport mechanisms described earlier, we provide evidence that the NCX plays a crucial role in the maintenance of [Ca 2þ ] i . Three chemically unrelated inhibitors of the NCX (bepridil, DCB (3 0 ,4 0 -dichlorobenzamil hydrochloride), and KB-R7943) all blocked human sperm motility in a dose and incubation time dependent manner. The IC 50 values for bepridil, DCB, and KB-R7943 were 16.2, 9.8, and 5.3 lM, respectively. The treatment with the above-mentioned blockers resulted in an elevated [Ca 2þ ] i and a decreased [Na þ ] i . The store-operated calcium channel (SOCC) inhibitor SKF 96365 also blocked the sperm motility (IC 50 ¼ 2.44 lM). The presence of the NCX antigen in the human spermatozoa was proven by flow cytometry, confocal laser scanning microscopy, and immunoblotting techniques. Calcium homeostasis of human spermatozoa is maintained by several transport proteins among which the SOCC and the NCX may play a major role.