Astrid Müller

The CatSper channel: a polymodal chemosensor in human sperm

The sperm‐specific CatSper channel controls the intracellular Ca2+ concentration ([Ca2+]i) and, thereby, the swimming behaviour of sperm. In humans, CatSper is directly activated by progesterone and prostaglandins—female factors that stimulate Ca2+ influx. Other factors including neurotransmitters, chemokines, and odorants also affect sperm function by changing [Ca2+]i. Several ligands, notably odorants, have been proposed to control Ca2+ entry and motility via G protein‐coupled receptors (GPCRs) and cAMP‐signalling pathways. Here, we show that odorants directly activate CatSper without involving GPCRs and cAMP. Moreover, membrane‐permeable analogues of cyclic nucleotides that have been frequently used to study cAMP‐mediated Ca2+ signalling also activate CatSper directly via an extracellular site. Thus, CatSper or associated protein(s) harbour promiscuous binding sites that can host various ligands. These results contest current concepts of Ca2+ signalling by GPCR and cAMP in mammalian sperm: ligands thought to activate metabotropic pathways, in fact, act via a common ionotropic mechanism. We propose that the CatSper channel complex serves as a polymodal sensor for multiple chemical cues that assist sperm during their voyage across the female genital tract.

Direct action of endocrine disrupting chemicals on human sperm

Synthetic endocrine disrupting chemicals (EDCs), omnipresent in food, household, and personal care products, have been implicated in adverse trends in human reproduction, including infertility and increasing demand for assisted reproduction. Here, we study the action of 96 ubiquitous EDCs on human sperm. We show that structurally diverse EDCs activate the sperm‐specific CatSper channel and, thereby, evoke an intracellular Ca2+ increase, a motility response, and acrosomal exocytosis. Moreover, EDCs desensitize sperm for physiological CatSper ligands and cooperate in low‐dose mixtures to elevate Ca2+ levels in sperm. We conclude that EDCs interfere with various sperm functions and, thereby, might impair human fertilization.

The Ca2+-activated K+ current of human sperm is mediated by Slo3

Sperm are equipped with a unique set of ion channels that orchestrate fertilization. In mouse sperm, the principal K+ current (IKSper) is carried by the Slo3 channel, which sets the membrane potential (Vm) in a strongly pHi-dependent manner. Here, we show that IKSper in human sperm is activated weakly by pHi and more strongly by Ca2+. Correspondingly, Vm is strongly regulated by Ca2+ and less so by pHi. We find that inhibitors of Slo3 suppress human IKSper, and we identify the Slo3 protein in the flagellum of human sperm. Moreover, heterologously expressed human Slo3, but not mouse Slo3, is activated by Ca2+ rather than by alkaline pHi; current–voltage relations of human Slo3 and human IKSper are similar. We conclude that Slo3 represents the principal K+ channel in human sperm that carries the Ca2+-activated IKSper current. We propose that, in human sperm, the progesterone-evoked Ca2+ influx carried by voltage-gated CatSper channels is limited by Ca2+-controlled hyperpolarization via Slo3. DOI: http://dx.doi.org/10.7554/eLife.01438.001

The CatSper channel controls chemosensation in sea urchin sperm

Sperm guidance is controlled by chemical and physical cues. In many species, Ca2+ bursts in the flagellum govern navigation to the egg. In Arbacia punctulata, a model system of sperm chemotaxis, a cGMP signaling pathway controls these Ca2+ bursts. The underlying Ca2+ channel and its mechanisms of activation are unknown. Here, we identify CatSper Ca2+ channels in the flagellum of A. punctulata sperm. We show that CatSper mediates the chemoattractant‐evoked Ca2+ influx and controls chemotactic steering; a concomitant alkalization serves as a highly cooperative mechanism that enables CatSper to transduce periodic voltage changes into Ca2+ bursts. Our results reveal intriguing phylogenetic commonalities but also variations between marine invertebrates and mammals regarding the function and control of CatSper. The variations probably reflect functional and mechanistic adaptations that evolved during the transition from external to internal fertilization.

High density and ligand affinity confer ultrasensitive signal detection by a guanylyl cyclase chemoreceptor

The sea urchin sperm guanylyl cyclase chemoreceptor achieves ultrasensitive signal detection and precise signal modulation through high receptor density, subnanomolar ligand affinity, and sequential dephosphorylation.

A K+-selective CNG channel orchestrates Ca2+ signalling in zebrafish sperm

Calcium in the flagellum controls sperm navigation. In sperm of marine invertebrates and mammals, Ca2+ signalling has been intensely studied, whereas for fish little is known. In sea urchin sperm, a cyclic nucleotide-gated K+ channel (CNGK) mediates a cGMP-induced hyperpolarization that evokes Ca2+ influx. Here, we identify in sperm of the freshwater fish Danio rerio a novel CNGK family member featuring non-canonical properties. It is located in the sperm head rather than the flagellum and is controlled by intracellular pH, but not cyclic nucleotides. Alkalization hyperpolarizes sperm and produces Ca2+ entry. Ca2+ induces spinning-like swimming, different from swimming of sperm from other species. The “spinning” mode probably guides sperm into the micropyle, a narrow entrance on the surface of fish eggs. A picture is emerging of sperm channel orthologues that employ different activation mechanisms and serve different functions. The channel inventories probably reflect adaptations to species-specific challenges during fertilization. DOI: http://dx.doi.org/10.7554/eLife.07624.001

Post‐translational cleavage of Hv1 in human sperm tunes pH‐ and voltage‐dependent gating

In human sperm, proton flux across the membrane is controlled by the voltage‐gated proton channel Hv1. We show that sperm harbour both Hv1 and an N‐terminally cleaved isoform termed Hv1Sper. The pH‐control of Hv1Sper and Hv1 is distinctively different. Hv1Sper and Hv1 can form heterodimers that combine features of both constituents. Cleavage and heterodimerization of Hv1 might represent an adaptation to the specific requirements of pH control in sperm.

Post-translational cleavage of Hv1 in human sperm tunes pH- and voltage-dependent gating: Hv1Sper in human sperm

In human sperm, proton flux across the membrane is controlled by the voltage‐gated proton channel Hv1. We show that sperm harbour both Hv1 and an N‐terminally cleaved isoform termed Hv1Sper. The pH‐control of Hv1Sper and Hv1 is distinctively different. Hv1Sper and Hv1 can form heterodimers that combine features of both constituents. Cleavage and heterodimerization of Hv1 might represent an adaptation to the specific requirements of pH control in sperm.

Post-translational cleavage of Hv1 in human sperm tunes pH- and voltage-dependent gatingPost-translational cleavage of Hv1 in human sperm tunes pH- and voltage-dependent gating

In human sperm, proton flux across the membrane is controlled by the voltage‐gated proton channel Hv1. We show that sperm harbour both Hv1 and an N‐terminally cleaved isoform termed Hv1Sper. The pH‐control of Hv1Sper and Hv1 is distinctively different. Hv1Sper and Hv1 can form heterodimers that combine features of both constituents. Cleavage and heterodimerization of Hv1 might represent an adaptation to the specific requirements of pH control in sperm.