Finasteride interferes with prostaglandin-induced CatSper signalling in human sperm

Ca2+ signalling controls human sperm functions necessary for successful fertilization. Multiple endocrine-disrupting chemicals have been found to activate the CatSper Ca2+ channel and thereby interfering with Ca2+ signalling in human sperm. Finasteride is prescribed to men in the fertile age to treat hair loss and its use has been associated with impaired male fertility. Due to the structural relatedness of finasteride to the endogenous CatSper ligand progesterone, this study aimed to investigate whether finasteride affects human sperm in a progestogen-like manner. The effect of finasteride on Ca2+ signalling via CatSper in human sperm was investigated in cell suspensions by single-cell imaging. Additionally, effects on sperm penetration into viscous medium and acrosome reaction were assessed. Finasteride alone caused a minor transient rise in the intracellular, free Ca2+ concentration ([Ca2+]i) at physiologically relevant concentrations. Ca2+ signals induced by PGE1 were inhibited by finasteride displaying mixed type of inhibition consistent with multiple binding sites. Finasteride did not interfere with progesterone-induced Ca2+ signalling and no effect on acrosome reaction or sperm viability was found. Finasteride significantly decreased PGE1-induced penetration into viscous medium but in concentrations above what is measured in blood and seminal fluids during regular finasteride administration. In conclusion, the use of finasteride may affect Ca2+ signalling in human sperm through an interaction with the PGE1-binding site, but to which extend it alters the chances of a successful fertilization needs further investigation. It remains to be investigated whether finasteride administration may give rise to side effects by interfering with prostaglandin signalling elsewhere in the human body.

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EDC IMPACT: Chemical UV filters can affect human sperm function in a progesterone-like manner

Endocrine Connections ◽

10.1530/ec-17-0156 ◽

2018 ◽

Vol 7 (1) ◽

pp. 16-25 ◽

Cited By ~ 13

Author(s):

A Rehfeld ◽

D L Egeberg ◽

K Almstrup ◽

J H Petersen ◽

S Dissing ◽

...

Keyword(s):

Acrosome Reaction ◽

Cell Function ◽

Human Sperm ◽

Cumulus Cells ◽

Viscous Medium ◽

Sperm Function ◽

Sperm Cells ◽

Uv Filters ◽

Sperm Penetration

Human sperm cell function must be precisely regulated to achieve natural fertilization. Progesterone released by the cumulus cells surrounding the egg induces a Ca2+ influx into human sperm cells via the CatSper Ca2+-channel and thereby controls sperm function. Multiple chemical UV filters have been shown to induce a Ca2+ influx through CatSper, thus mimicking the effect of progesterone on Ca2+ signaling. We hypothesized that these UV filters could also mimic the effect of progesterone on sperm function. We examined 29 UV filters allowed in sunscreens in the US and/or EU for their ability to affect acrosome reaction, penetration, hyperactivation and viability in human sperm cells. We found that, similar to progesterone, the UV filters 4-MBC, 3-BC, Meradimate, Octisalate, BCSA, HMS and OD-PABA induced acrosome reaction and 3-BC increased sperm penetration into a viscous medium. The capacity of the UV filters to induce acrosome reaction and increase sperm penetration was positively associated with the ability of the UV filters to induce a Ca2+ influx. None of the UV filters induced significant changes in the proportion of hyperactivated cells. In conclusion, chemical UV filters that mimic the effect of progesterone on Ca2+ signaling in human sperm cells can similarly mimic the effect of progesterone on acrosome reaction and sperm penetration. Human exposure to these chemical UV filters may impair fertility by interfering with sperm function, e.g. through induction of premature acrosome reaction. Further studies are needed to confirm the results in vivo.

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Expression and function of ras proto-oncogene proteins in human sperm cells

Journal of Cell Science ◽

10.1242/jcs.102.3.487 ◽

1992 ◽

Vol 102 (3) ◽

pp. 487-494 ◽

Cited By ~ 1

Author(s):

R.K. Naz ◽

K. Ahmad ◽

P. Kaplan

Keyword(s):

Sperm Cell ◽

Acrosome Reaction ◽

Cell Function ◽

Beat Frequency ◽

Human Sperm ◽

Sperm Cells ◽

Ras Protein ◽

Head Displacement ◽

Sperm Penetration ◽

And Function

The presence and role of c-ras proteins were investigated in mature human sperm cells. The v-H-ras monoclonal antibody (mAb) against the c-ras protein, p21, reacted specifically with the acrosomal region of methanol-fixed as well as unfixed-live capacitated and non-capacitated human sperm cell in the indirect immunofluorescence technique. The v-H-ras mAb predominantly recognized c-ras protein of 21 kDa on the Western blot of lithium diiodosalicylate (LIS)-solubilized human sperm preparation. The incubation of sperm cells with v-H-ras mAb affected the sperm cell function in the human sperm penetration assay. The antibody significantly reduced the acrosome reaction and release of acrosin activity from the sperm cells. There was no effect of the mAb on percentage motility, although the mAb significantly affected various motility characteristics such as linearity, amplitude of lateral head displacement (ALH) and beat frequency, the motility parameters involved in the hyperactivation phenomenon of sperm cells leading to capacitation and acrosome reaction. These results suggest that the c-ras or c-ras-like proteins are present in mature sperm cell and may have a role in capacitation and/or acrosome reaction of human sperm cell.

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Faculty Opinions recommendation of Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5804956.5786054 ◽

2010 ◽

Author(s):

Edward Bertaccini

Keyword(s):

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Binding Sites ◽

Transmembrane Domain ◽

General Anesthetic ◽

Nicotinic Acetylcholine ◽

Multiple Binding Sites ◽

Multiple Binding

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NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191011095341 ◽

2019 ◽

Vol 19 (24) ◽

pp. 2239-2253 ◽

Cited By ~ 2

Author(s):

Paul J. Goldsmith

Keyword(s):

Binding Sites ◽

Receptor Activation ◽

Research Area ◽

Allosteric Modulators ◽

Nonselective Cation Channels ◽

Multiple Binding Sites ◽

Multiple Binding ◽

Excitatory Neurotransmission ◽

Psychiatric Conditions ◽

High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

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Effects of Multiple Binding Sites on Studies of Hydrogen Bonding between Nitroxide Radicals and Solvent Molecules

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19930047 ◽

1993 ◽

Vol 58 (1) ◽

pp. 47-52 ◽

Cited By ~ 2

Author(s):

Imad Al-Bala'a ◽

Richard D. Bates

Keyword(s):

Hydrogen Bonding ◽

Magnetic Resonance ◽

Binding Site ◽

Binding Sites ◽

Hyperfine Coupling Constant ◽

Hydrogen Donor ◽

Complex Formation Constants ◽

Multiple Binding Sites ◽

Multiple Binding ◽

Solvent Molecules

The role of more than one binding site on a nitroxide free radical in magnetic resonance determinations of the properties of the complex formed with a hydrogen donor is examined. The expression that relates observed hyperfine couplings in EPR spectra to complex formation constants and concentrations of each species in solution becomes much more complex when multiple binding sites are present, but reduces to a simpler form when binding at the two sites occurs independently and the binding at the non-nitroxide site does not produce significant differences in the hyperfine coupling constant in the complexed radical. Effects on studies of hydrogen bonding between multiple binding site nitroxides and hydrogen donor solvent molecules by other magnetic resonance methods are potentially more extreme.

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Cryo-EM structure of human Wntless in complex with Wnt3a

Nature Communications ◽

10.1038/s41467-021-24731-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Qing Zhong ◽

Yanyu Zhao ◽

Fangfei Ye ◽

Zaiyu Xiao ◽

Gaoxingyu Huang ◽

...

Keyword(s):

Transmembrane Domain ◽

Transmembrane Protein ◽

Multiple Interfaces ◽

Wnt Proteins ◽

Binding Partners ◽

Multiple Binding Sites ◽

Evolutionarily Conserved ◽

Multiple Binding ◽

Hydrophobic Tunnel ◽

Conserved Core

AbstractWntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.

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