The role of Hv1 and CatSper channels in sperm activation

Abstract

Elevations of sperm intracellular pH and Ca(2+) regulate sperm motility, chemotaxis, capacitation and the acrosome reaction, and play a vital role in the ability of the sperm cell to reach and fertilise the egg. In human spermatozoa, the flagellar voltage-gated proton channel Hv1 is the main H(+) extrusion pathway that controls sperm intracellular pH, and the pH-dependent flagellar Ca²(+) channel CatSper is the main pathway for Ca²(+) entry as measured by the whole-cell patch clamp technique. Hv1 and CatSper channels are co-localized within the principal piece of the sperm flagellum. Hv1 is dedicated to proton extrusion from flagellum and is activated by membrane depolarisation, an alkaline extracellular environment, the endocannabinoid anandamide, and removal of extracellular zinc, a potent Hv1 blocker. The CatSper channel is strongly potentiated by intracellular alkalinisation. Since Hv1 and CatSper channels are located in the same subcellular domain, proton extrusion via Hv1 channels should induce intraflagellar alkalinisation and activate CatSper ion channels. Therefore the combined action of Hv1 and CatSper channels in human spermatozoa can induce elevation of both intracellular pH and Ca²(+) required for sperm activation in the female reproductive tract. Here, we discuss how Hv1 and CatSper channels regulate human sperm physiology and the differences in control of sperm intracellular pH and Ca²(+) between species.

Yuriy Kirichok is an Assistant Professor of Physiology at the University of California San Francisco. He graduated from Moscow Institute of Physics and Technology, Russia and received his PhD in Biophysics from Bogomoletz Institute of Physiology, Kiev, Ukraine. He then moved to Boston, MA where he joined Dr David Clapham's Lab at Harvard Medical School as a postdoctoral fellow. He studies the role of ion channels in male fertility and ion channels that regulate mitochondria function. He adores the patch-clamp technique and can apply it to virtually any object no matter how small it is or how fast it moves. Polina Lishko graduated from Taras Shevchenko National University, Kiev, Ukraine and received her PhD in Biophysics from Bogomoletz Institute of Physiology, Kiev, Ukraine. In 2000 she joined Vadim Arshavsky's laboratory at Harvard Medical School to study mechanisms of vertebrate phototransduction. She continued her postdoctoral training to study the structure–function relationship of TRPV ion channels in Rachelle Gaudet's laboratory at Harvard University. She is currently a Specialist at the University of California San Francisco and together with Yuriy Kirichok, who happens to be her husband, studies regulation of sperm ion channels in humans. Her other interests include the history of science, cooking, and gardening.

Figure 1. Proton regulation and CatSper function in mouse versus human spermatozoa

In mouse spermatozoa, intracellular alkalinisation is achieved via activity of Na⁺-dependent (Cl⁻/HCO₃⁻) exchanger (NCB) and sperm-specific Na⁺/H⁺ exchanger (sNHE). NCB also helps to accumulate bicarbonate ions (HCO₃⁻) to stimulate bicarbonate-dependent atypical adenylyl cyclase (ADCY10), which leads to elevation of intracellular cAMP (Hess et al. 2005; Carlson et al. 2007) and possible stimulation of sNHE, which has a cAMP binding site (Wang et al. 2003). In human spermatozoa, the voltage-gated proton channel Hv1 is likely to constitute the main proton extrusion mechanism. Activation of Hv1 by anandamide (AEA), removal of extracellular zinc, and the alkaline environment of the female reproductive tract cause intracellular alkalisation. In both mouse and human sperm cells, intracellular alkalinisation activates the calcium channel CatSper that allows calcium ions to enter sperm flagellum. The rise in intracellular calcium causes hyperactivation and prepares spermatozoa to undergo the acrosome reaction.