The control of male fertility by spermatozoan ion channels

Abstract

Ion channels control the sperm ability to fertilize the egg by regulating sperm maturation in the female reproductive tract and by triggering key sperm physiological responses required for successful fertilization such as hyperactivated motility, chemotaxis, and the acrosome reaction. CatSper, a pH-regulated, calcium-selective ion channel, and KSper (Slo3) are core regulators of sperm tail calcium entry and sperm hyperactivated motility. Many other channels had been proposed as regulating sperm activity without direct measurements. With the development of the sperm patch-clamp technique, CatSper and KSper have been confirmed as the primary spermatozoan ion channels. In addition, the voltage-gated proton channel Hv1 has been identified in human sperm tail, and the P2X2 ion channel has been identified in the midpiece of mouse sperm. Mutations and deletions in sperm-specific ion channels affect male fertility in both mice and humans without affecting other physiological functions. The uniqueness of sperm ion channels makes them ideal pharmaceutical targets for contraception. In this review we discuss how ion channels regulate sperm physiology.

Figure 1

Mammalian spermatozoa. (a) Schematic representation of mammalian sperm. (b) Comparison between human and mouse spermatozoa. (c) Human spermatozoa with head, midpiece, and principal piece as indicated. (d ) Cytoplasmic droplet and annulus are labeled.

Figure 2

Sperm ion channel localization and function. Flagellar beating is regulated by at least three ion channels: alkaline-sensitive CatSper (Ca²⁺ entry), pH-regulated Slo3 (K⁺ exit), and Hv1 (H⁺ exit; human sperm only). The upper half of the figure depicts ion channels and their regulation as detected in human sperm (the regulation of the CatSper complex by progesterone and Hv1), whereas the lower half of the figure shows ion channels found in mouse spermatozoa (CatSper complex, Slo3, and P2X2).

Figure 3

Regulation of flagellar Ca²⁺. Ca²⁺ enters the sperm flagellum via the alkaline-activated CatSper channel and is extruded from the flagellum by a plasma membrane Ca²⁺-ATPase (42). Ca²⁺-ATPase pumps hydrolyze ATP to export a cytoplasmic Ca²⁺ ion and to import extracellular protons. The resulting acidification of flagellar cytoplasm must be prevented by proton extrusion via channels or transporters.

Figure 4

Regulation of flagellar pH. Protons may accumulate in the sperm flagellum via proton exchange, ATP hydrolysis by axonemal dynein, and active glycolysis. Rapid proton extrusion from the human sperm flagella may be carried out by Hv1 proteins, which form a proton-selective, voltage-gated ion channel restricted to the sperm’s principal piece.