The antidepressant Sertraline inhibits CatSper Ca2+ channels in human sperm

Abstract

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. WHAT IS KNOWN ALREADY In 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, DURATION We 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, METHODS The 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 CHANCE Several 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 CAUTION This is an in vitro study. Future studies have to assess the physiological relevance in vivo. WIDER IMPLICATIONS OF THE FINDINGS The 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 NUMBER NA.

SKF96365 modulates activity of CatSper channels in human sperm

“…Dual actions of drugs (e.g. RU1968, sertraline) on [Ca 2+ ] i in human sperm, apparently reflecting an initial stimulation of CatSper, lasting a few minutes, followed by a tonic inhibitory effect, have been described previously ( Rennhack et al , 2018 ; Rahban et al , 2021 ). The transient nature of the increase in CatSper current (60–100 s; Fig.…”

Unexplained infertility is frequently caused by defective CatSper function preventing sperm from penetrating the egg coat

“…In the presence of progesterone, the number of control sperm was enhanced by 1.7- fold (Fig. 7B, C), confirming that progesterone facilitates the migration into viscous medium (Brown et al ., 2017; Luo et al ., 2019; Rahban et al ., 2021; Rehfeld et al ., 2020; Williams et al ., 2015). This action of progesterone was abolished in CATSPER2 -/- sperm (Fig.…”

“…8B), confirming that it is not per se affected by loss of CatSper function (Luo et al ., 2019); see however (Wang et al ., 2021b). To elucidate the role of Ca 2+ influx via CatSper, we studied the action of progesterone, which in most (Harper et al ., 2006; Krausz et al ., 1996; Luo et al ., 2019; Rahban et al ., 2021; Rehfeld et al ., 2020; Rennhack et al ., 2018; Schaefer et al ., 1998; Tamburrino et al ., 2014) but not all (Prajapati et al ., 2022; Uhler et al ., 1992) previous studies sufficed as a physiological stimulus for acrosomal exocytosis and was abolished in sperm lacking functional CatSper (Luo et al ., 2019). Under the experimental conditions used here, the fraction of acrosome reacted control sperm was not significantly enhanced by progesterone (Fig.…”

High-throughput screening method for discovering CatSper inhibitors using membrane depolarization caused by external calcium chelation and fluorescent cell barcoding

“…It is well established that CatSper regulation is promiscuous since it can be non-specifically inhibited or activated by numerous compounds ( Rennhack et al, 2018 ; Rahban et al, 2021 ). This channel’s intrinsic feature makes it challenging to discover specific candidates to inhibit its function.…”