Dataset Information

Chemosensory Ca2+ dynamics correlate with diverse behavioral phenotypes in human sperm.

ABSTRACT: In the female reproductive tract, mammalian sperm undergo a regulated sequence of prefusion changes that "prime" sperm for fertilization. Among the least understood of these complex processes are the molecular mechanisms that underlie sperm guidance by environmental chemical cues. A "hard-wired" Ca(2+) signaling strategy that orchestrates specific motility patterns according to given functional requirements is an emerging concept for regulation of sperm swimming behavior. The molecular players involved, the spatiotemporal characteristics of such motility-associated Ca(2+) dynamics, and the relation between a distinct Ca(2+) signaling pattern and a behavioral sperm phenotype, however, remain largely unclear. Here, we report the functional characterization of two human sperm chemoreceptors. Using complementary molecular, physiological, and behavioral approaches, we comparatively describe sperm Ca(2+) responses to specific agonists of these novel receptors and bourgeonal, a known sperm chemoattractant. We further show that individual receptor activation induces specific Ca(2+) signaling patterns with unique spatiotemporal dynamics. These distinct Ca(2+) dynamics are correlated to a set of stimulus-specific stereotyped behavioral responses that could play vital roles during various stages of prefusion sperm-egg chemical communication.

SUBMITTER: Veitinger T

PROVIDER: S-EPMC3089573 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Chemosensory Ca2+ dynamics correlate with diverse behavioral phenotypes in human sperm.

Veitinger Thomas T Riffell Jeffrey R JR Veitinger Sophie S Nascimento Jaclyn M JM Triller Annika A Chandsawangbhuwana Charlie C Schwane Katlen K Geerts Andreas A Wunder Frank F Berns Michael W MW Neuhaus Eva M EM Zimmer Richard K RK Spehr Marc M Hatt Hanns H

The Journal of biological chemistry 20110321 19

In the female reproductive tract, mammalian sperm undergo a regulated sequence of prefusion changes that "prime" sperm for fertilization. Among the least understood of these complex processes are the molecular mechanisms that underlie sperm guidance by environmental chemical cues. A "hard-wired" Ca(2+) signaling strategy that orchestrates specific motility patterns according to given functional requirements is an emerging concept for regulation of sperm swimming behavior. The molecular players i ...[more]

PMID: 21454470

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Project description:Study questionDo selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?Summary answerThe SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.What is known alreadyIn human sperm, CatSper translates changes of the chemical microenvironment into changes of the intracellular Ca2+ concentration ([Ca2+]i) and swimming behavior. CatSper is promiscuously activated by oviductal ligands, but also by synthetic chemicals that might disturb the fertilization process. It is well known that SSRIs have off-target actions on Ca2+, Na+ and K+ channels in somatic cells. Whether SSRIs affect the activity of CatSper is, however, unknown.Study design, size, durationWe studied the action of the seven drugs belonging to the most commonly prescribed class of antidepressants, SSRIs, on resting [Ca2+]i and Ca2+ influx via CatSper in human sperm. The SSRI Sertraline was selected for in-depth analysis of its action on steroid-, prostaglandin-, pH- and voltage-activation of human CatSper. Moreover, the action of Sertraline on sperm acrosomal exocytosis and penetration into viscous media was evaluated.Participants/materials, setting, methodsThe activity of CatSper was investigated in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. Acrosomal exocytosis was investigated using Pisum sativum agglutinin and image cytometry. Sperm penetration in viscous media was evaluated using the Kremer test.Main results and the role of chanceSeveral SSRIs affected [Ca2+]i and attenuated ligand-induced Ca2+ influx via CatSper. In particular, the SSRI Sertraline almost completely suppressed Ca2+ influx via CatSper. Remarkably, the drug was about four-fold more potent to suppress prostaglandin- versus steroid-induced Ca2+ influx. Sertraline also suppressed alkaline- and voltage-activation of CatSper, indicating that the drug directly inhibits the channel. Finally, Sertraline impaired ligand-induced acrosome reaction and sperm penetration into viscous media.Limitations, reasons for cautionThis is an in vitro study. Future studies have to assess the physiological relevance in vivo.Wider implications of the findingsThe off-target action of Sertraline on CatSper in human sperm might impair the fertilization process. In a research setting, Sertraline may be used to selectively inhibit prostaglandin-induced Ca2+ influx.Study funding/competing interest(s)This work was supported by the Swiss Centre for Applied Human Toxicology (SCAHT), the Département de l'Instruction Publique of the State of Geneva, the German Research Foundation (CRU326), the Interdisciplinary Center for Clinical Research, Münster (IZKF; Str/014/21), the Innovation Fund Denmark (grant numbers 14-2013-4) and the EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation. The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.Trial registration numberNA.

Project description:Understanding how spermatozoa approach the egg is a central biological issue. Recently a considerable amount of experimental evidence has accumulated on the relation between oscillations in intracellular calcium ion concentration ([Ca2+]i) in the sea urchin sperm flagellum, triggered by peptides secreted from the egg, and sperm motility. Determination of the structure and dynamics of the signaling pathway leading to these oscillations is a fundamental problem. However, a biochemically based formulation for the comprehension of the molecular mechanisms operating in the axoneme as a response to external stimulus is still lacking. Based on experiments on the S. purpuratus sea urchin spermatozoa, we propose a signaling network model where nodes are discrete variables corresponding to the pathway elements and the signal transmission takes place at discrete time intervals according to logical rules. The validity of this model is corroborated by reproducing previous empirically determined signaling features. Prompted by the model predictions we performed experiments which identified novel characteristics of the signaling pathway. We uncovered the role of a high voltage-activated Ca2+ channel as a regulator of the delay in the onset of fluctuations after activation of the signaling cascade. This delay time has recently been shown to be an important regulatory factor for sea urchin sperm reorientation. Another finding is the participation of a voltage-dependent calcium-activated K+ channel in the determination of the period of the [Ca2+]i fluctuations. Furthermore, by analyzing the spread of network perturbations we find that it operates in a dynamically critical regime. Our work demonstrates that a coarse-grained approach to the dynamics of the signaling pathway is capable of revealing regulatory sperm navigation elements and provides insight, in terms of criticality, on the concurrence of the high robustness and adaptability that the reproduction processes are predicted to have developed throughout evolution.

Dataset Information

Chemosensory Ca2+ dynamics correlate with diverse behavioral phenotypes in human sperm.

Publications

Chemosensory Ca2+ dynamics correlate with diverse behavioral phenotypes in human sperm.

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