The sperm-specific K channel Slo3 is inhibited by albumin and steroids contained in reproductive fluids.

To locate and fertilize the egg, sperm probe the varying microenvironment prevailing at different stages during their journey across the female genital tract. To this end, they are equipped with a unique repertoire of mostly sperm-specific proteins. In particular, the flagellar Ca channel CatSper has come into focus as a polymodal sensor used by human sperm to register ligands released into the female genital tract.

Evaluation of SK-N-SH Cells as a Model for NMDA Receptor Induced Toxicity.

Background/aims: Over the years, the number of patients with neurodegenerative diseases is constantly rising illustrating the need for new neuroprotective drugs. A promising treatment approach is the reduction of excitotoxicity induced by rising ()-glutamate levels and subsequent NMDA receptor overactivation. To facilitate the search for new NMDA receptor inhibitors neuronal cell models are needed.

Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation.

The infertility of many couples rests on an enigmatic dysfunction of the man's sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of men with normal semen parameters but defective CatSper function.

Cylicins are a structural component of the sperm calyx being indispensable for male fertility in mice and human.

Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 () and the autosomal Cylicin 2 () genes, have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats.

Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives.

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications.

Pathogenic gene variants in , , , , and cause defects of sperm flagella composition and male infertility.

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder affecting the function of motile cilia in several organ systems. In PCD, male infertility is caused by defective sperm flagella composition or deficient motile cilia function in the efferent ducts of the male reproductive system. Different PCD-associated genes encoding axonemal components involved in the regulation of ciliary and flagellar beating are also reported to cause infertility due to multiple morphological abnormalities of the sperm flagella (MMAF).

Synthesis and Functional Characterization of Novel RU1968-Derived CatSper Inhibitors with Reduced Stereochemical Complexity.

The sperm-specific Ca channel CatSper (cation channel of sperm) controls the intracellular Ca concentration and, thereby, the swimming behavior of sperm from many species. The steroidal ethylenediamine RU1968 () represents a well-characterized, potent, and fairly selective cross-species inhibitor of CatSper. Due to its two additional centers of chirality in the amine-bearing side chain, RU1968 is a mixture of diastereomeric pairs of enantiomers and, thus, difficult to synthesize.

Simultaneous recording of multiple cellular signaling events by frequency- and spectrally-tuned multiplexing of fluorescent probes.

Fluorescent probes that change their spectral properties upon binding to small biomolecules, ions, or changes in the membrane potential (V) are invaluable tools to study cellular signaling pathways. Here, we introduce a novel technique for simultaneous recording of multiple probes at millisecond time resolution: (FAST). Different from present multiplexing approaches, FAST uses phase-sensitive signal detection, which renders various combinations of common probes for V and ions accessible for multiplexing.

The antidepressant Sertraline inhibits CatSper Ca2+ channels in human sperm.

Study Question: Do selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?

Summary Answer: The SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.

The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn on CatSper Ca Channels in Human Sperm.

The sperm-specific Ca channel CatSper registers chemical cues that assist human sperm to fertilize the egg. Prime examples are progesterone and prostaglandin E that activate CatSper without involving classical nuclear and G protein-coupled receptors, respectively. Here, we study the action of seminal and follicular fluid as well of the contained individual prostaglandins and steroids on the intracellular Ca concentration of sperm from donors and -deficient patients that lack functional CatSper channels.

Molecular Mechanism Underlying the Action of Glycoproteins on Mouse Sperm.

Mammalian oocytes are enveloped by the zona pellucida (ZP), an extracellular matrix of glycoproteins. In sperm, stimulation with ZP proteins evokes a rapid Ca influx via the sperm-specific, pH-sensitive Ca channel CatSper. However, the physiological role and molecular mechanisms underlying ZP-dependent activation of CatSper are unknown.

The Ca channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA.

The sperm-specific Ca channel CatSper (cation channel of sperm) controls the influx of Ca into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing activation of PKA is, however, a matter of controversy.

Challenging human somatic testicular cell reassembly by protein kinase inhibition -setting up a functional in vitro test system.

Signalling pathways and cellular interactions defining initial processes of testis morphogenesis, i.e. cord formation, are poorly understood.

Rotational motion and rheotaxis of human sperm do not require functional CatSper channels and transmembrane Ca signaling.

Navigation of sperm in fluid flow, called rheotaxis, provides long-range guidance in the mammalian oviduct. The rotation of sperm around their longitudinal axis (rolling) promotes rheotaxis. Whether sperm rolling and rheotaxis require calcium (Ca ) influx via the sperm-specific Ca channel CatSper, or rather represent passive biomechanical and hydrodynamic processes, has remained controversial.

Kinetic and photonic techniques to study chemotactic signaling in sea urchin sperm.

Sperm from sea urchins are attracted by chemical cues released by the egg-a mechanism called chemotaxis. We describe here the signaling pathway and molecular components endowing sperm with single-molecule sensitivity. Chemotactic signaling and behavioral responses occur on a timescale of a few milliseconds to seconds.

An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis.

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane.

CRISP2 Is a Regulator of Multiple Aspects of Sperm Function and Male Fertility.

The cysteine-rich secretory proteins (CRISPs) are a group of proteins that show a pronounced expression biased to the male reproductive tract. Although sperm encounter CRISPs at virtually all phases of sperm development and maturation, CRISP2 is the sole CRISP produced during spermatogenesis, wherein it is incorporated into the developing sperm head and tail. In this study we tested the necessity for CRISP2 in male fertility using Crisp2 loss-of-function mouse models.

Synergistic activation of CatSper Ca2+ channels in human sperm by oviductal ligands and endocrine disrupting chemicals.

Study Question: Does the chemosensory activation of CatSper Ca2+ channels in human sperm give rise to additive, sub-additive or even synergistic actions among agonists?

Summary Answer: We show that oviductal ligands and endocrine disrupting chemicals (EDCs) activate human CatSper highly synergistically.

What Is Known Already: In human sperm, the sperm-specific CatSper channel controls the intracellular Ca2+ concentration and, thereby, several crucial stages toward fertilization. CatSper is activated by oviductal ligands and structurally diverse EDCs.

A novel cross-species inhibitor to study the function of CatSper Ca channels in sperm.

Background And Purpose: Sperm from many species share the sperm-specific Ca channel CatSper that controls the intracellular Ca concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling the activity of CatSper and its role during fertilization differ among species. A lack of suitable pharmacological tools has hampered the elucidation of the function of CatSper.

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

Key Points: 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.

Sperm navigation along helical paths in 3D chemoattractant landscapes.

Sperm require a sense of direction to locate the egg for fertilization. They follow gradients of chemical and physical cues provided by the egg or the oviduct. However, the principles underlying three-dimensional (3D) navigation in chemical landscapes are unknown.

The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation.

Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adaptor ASC and the assembly of ASC specks. ASC specks recruit and activate caspase-1, which induces maturation of the cytokine interleukin 1β (IL-1β) and pyroptotic cell death. Here we found that after pyroptosis, ASC specks accumulated in the extracellular space, where they promoted further maturation of IL-1β.

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 Ca(2+) increase, a motility response, and acrosomal exocytosis.

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 Ca(2+).