Research progress on ion channels and their molecular regulatory mechanisms in the human sperm flagellum

Abstract

The ion channels in sperm tail play an important role in triggering key physiological reactions, e.g., progressive motility, hyperactivation, required for successful fertilization. Among them, CatSper and KSper have been shown to be important ion channels for the transport of Ca2+ and K+. Moreover, the voltage‐gated proton channel Hv1, the sperm‐specific sodium‐hydrogen exchanger (sNHE), the epithelial sodium channel (ENaC), members of the temperature‐sensitive TRP channel family, and the cystic fibrosis transmembrane regulator (CFTR) are also found in the flagellum. This review focuses on the latest advances in ion channels located at the flagellum, describes how they affect sperm physiological function, and summarizes some primary mutual regulation mechanism between ion channels, including PH, membrane potential, and cAMP. These ion channels may be promising targets for clinical application in infertility.

Identification of a Novel Structural Class of HV1 Inhibitors by Structure-Based Virtual Screening

“…2,12,17,18 Upon membrane depolarization, these amino acid residues move outward, resulting in channel opening and proton conduction. 11,12,14 In voltage-gated proton channels, only the open or closed states can be distinguished; there is no inactivation mechanism. 6,19 H V 1 channels are involved in many signaling pathways, and their most important role is the regulation of the intracellular pH.…”

“…Voltage-gated proton channel 1 (H V 1) is a transmembrane protein that was first described more than 30 years ago, however, the channel gene ( hvcn1, hydrogen voltage-gated channel 1) was not identified until 2006. − H V 1 is expressed in various immune cells, skeletal muscle cells, oocytes, osteoclasts, blood cells, sperm cells and DRG neurons. ,− H V 1 channels are exclusively selective for protons, conducted through the voltage sensing domain (VSD), in which aspartate and arginine residues are responsible for the high proton selectivity. ,,, Moreover, these channels can detect changes in membrane potential and open their conduction pathway as a result of membrane depolarization and subsequent conformational changes …”

“…The S5–S6 pore-forming domain found in other voltage-gated ion channels is absent in H V 1, resulting in the proton-selective permeation pathway being located within the S1–S4 transmembrane segments . In most species, the channel operates as a homodimer, and each monomer has its own voltage sensor, pH sensor, and proton permeation pathway and can function independently. , Voltage sensitivity is conferred by the S4 segment, which contains three positively charged arginine residues, Arg205, Arg208, and Arg211. ,,, Upon membrane depolarization, these amino acid residues move outward, resulting in channel opening and proton conduction. ,, In voltage-gated proton channels, only the open or closed states can be distinguished; there is no inactivation mechanism. , …”

“… 1 , 5 − 13 H V 1 channels are exclusively selective for protons, conducted through the voltage sensing domain (VSD), in which aspartate and arginine residues are responsible for the high proton selectivity. 1 , 11 , 12 , 14 Moreover, these channels can detect changes in membrane potential and open their conduction pathway as a result of membrane depolarization and subsequent conformational changes. 11 …”

“… 15 , 16 Voltage sensitivity is conferred by the S4 segment, which contains three positively charged arginine residues, Arg205, Arg208, and Arg211. 2 , 12 , 17 , 18 Upon membrane depolarization, these amino acid residues move outward, resulting in channel opening and proton conduction. 11 , 12 , 14 In voltage-gated proton channels, only the open or closed states can be distinguished; there is no inactivation mechanism.…”