Na+/H+ Exchangers (NHEs) in Mammalian Sperm: Essential Contributors to Male Fertility

Abstract

Na+/H+ exchangers (NHEs) are known to be important regulators of pH in multiple intracellular compartments of eukaryotic cells. Sperm function is especially dependent on changes in pH and thus it has been postulated that NHEs play important roles in regulating the intracellular pH of these cells. For example, in order to achieve fertilization, mature sperm must maintain a basal pH in the male reproductive tract and then alkalize in response to specific signals in the female reproductive tract during the capacitation process. Eight NHE isoforms are expressed in mammalian testis/sperm: NHE1, NHE3, NHE5, NHE8, NHA1, NHA2, NHE10, and NHE11. These NHE isoforms are expressed at varying times during spermatogenesis and localize to different subcellular structures in developing and mature sperm where they contribute to multiple aspects of sperm physiology and male fertility including proper sperm development/morphogenesis, motility, capacitation, and the acrosome reaction. Previous work has provided evidence for NHE3, NHE8, NHA1, NHA2, and NHE10 being critical for male fertility in mice and NHE10 has recently been shown to be essential for male fertility in humans. In this article we review what is known about each NHE isoform expressed in mammalian sperm and discuss the physiological significance of each NHE isoform with respect to male fertility.

pH Homeodynamics and Male Fertility: A Coordinated Regulation of Acid-Based Balance during Sperm Journey to Fertilization

“…NHEs regulate the acid-base balance of a wide range of luminal fluids. Several NHEs have been detected in the male reproductive tract or spermatozoa, including NHE1, NHE2, NHE3, NHE5, NHE8, NHA1, NHA2, and sNHE [ 39 ].…”

“…NHE2 is localized in the caput, corpus, and cauda of the epididymis, and in the vas deferens and testes [ 159 , 160 ]; however, limited information is available regarding its function. NHE3 is expressed in the efferent ducts and proximal epididymis in rats and is localized to the efferent ducts in humans and mice, where it is involved in the reabsorption of Na + and in regulating luminal fluid pH [ 38 , 39 ].…”

“…Knockdown of Nhe3 results in abnormal dilation of the rete testis lumen and efferent ducts, leading to obstructive azoospermia [ 39 ]. In spermatogenic cells, NHE3 is localized explicitly to developing acrosomal granules, and its absence results in severe defects in the acrosome, indicating that NHE3 is essential for normal acrosome development [ 40 ].…”

The sodium-proton exchangers sNHE and NHE1 control plasma membrane hyperpolarization in mouse sperm

“…The principal membrane H + transporters responsible for mediating H + efflux in response to the rising extracellular pH within the female reproductive tract are Na +/ H + exchangers (NHEs) (for a review see 7 ). Three groups identify NHE isoforms in mammalian sperm: NHE1 and NHE5 (SLC9A subgroup), NHA1 and NHA2 (SLC9B subgroup), and sNHE as a member of the SLC9C subgroup, with the recent identification of SLC9C2 in at least rat and human sperm 8,9 . Their roles and significance in sperm physiology remain an active area of research.…”

“…Given the importance of sperm Em hyperpolarization associated to SLO3 currents, it is intriguing that the molecular events leading to SLO3 opening have not been completely revealed yet, besides knowing that SLO3 responds to alkalinization.The principal membrane H + transporters responsible for mediating H + efflux in response to the rising extracellular pH within the female reproductive tract are Na +/ H + exchangers (NHEs) (for a review see 7 ). Three groups identify NHE isoforms in mammalian sperm: NHE1 and NHE5 (SLC9A subgroup), NHA1 and NHA2 (SLC9B subgroup), and sNHE as a member of the SLC9C subgroup, with the recent identification of SLC9C2 in at least rat and human sperm 8,9 . Their roles and significance in sperm physiology remain an active area of research.The localization of NHE1 to the sperm midpiece is established 10 , but its precise contribution to sperm fertility has been somewhat enigmatic.…”