Role and Modulation of TRPV1 in Mammalian Spermatozoa: An Updated Review.
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ABSTRACT:
SUBMITTER: Ramal-Sanchez M
PROVIDER: S-EPMC8122410 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: During their transit through the female genital tract, sperm have to recognize and discriminate numerous chemical compounds. However, our current knowledge of the molecular identity of appropriate chemosensory receptor proteins in sperm is still rudimentary. Considering that members of the Tas1r family of taste receptors are able to discriminate between a broad diversity of hydrophilic chemosensory substances, the expression of taste receptors in mammalian spermatozoa was examined. METHODOLOGY/PRINCIPAL FINDINGS: The present manuscript documents that Tas1r1 and Tas1r3, which form the functional receptor for monosodium glutamate (umami) in taste buds on the tongue, are expressed in murine and human spermatozoa, where their localization is restricted to distinct segments of the flagellum and the acrosomal cap of the sperm head. Employing a Tas1r1-deficient mCherry reporter mouse strain, we found that Tas1r1 gene deletion resulted in spermatogenic abnormalities. In addition, a significant increase in spontaneous acrosomal reaction was observed in Tas1r1 null mutant sperm whereas acrosomal secretion triggered by isolated zona pellucida or the Ca²? ionophore A23187 was not different from wild-type spermatozoa. Remarkably, cytosolic Ca²? levels in freshly isolated Tas1r1-deficient sperm were significantly higher compared to wild-type cells. Moreover, a significantly higher basal cAMP concentration was detected in freshly isolated Tas1r1-deficient epididymal spermatozoa, whereas upon inhibition of phosphodiesterase or sperm capacitation, the amount of cAMP was not different between both genotypes. CONCLUSIONS/SIGNIFICANCE: Since Ca²? and cAMP control fundamental processes during the sequential process of fertilization, we propose that the identified taste receptors and coupled signaling cascades keep sperm in a chronically quiescent state until they arrive in the vicinity of the egg - either by constitutive receptor activity and/or by tonic receptor activation by gradients of diverse chemical compounds in different compartments of the female reproductive tract.
| S-EPMC3303551 | biostudies-literature
Project description:The molecular bases of sperm thermotaxis, the temperature-oriented cell motility, are currently under investigation. Thermal perception relies on a subclass of the transient receptor potential [TRP] channels, whose member TRPV1 is acknowledged as the heat sensing receptor. Here we investigated the involvement of TRPV1 in human sperm thermotaxis. We obtained semen samples from 16 normozoospermic subjects attending an infertility survey programme, testis biopsies from 6 patients with testicular germ cell cancer and testis fine needle aspirates from 6 patients with obstructive azoospermia undergoing assisted reproductive technologies. Expression of TRPV1 mRNA was assessed by RT-PCR. Protein expression of TRPV1 was determined by western blot, flow cytometry and immunofluorescence. Sperm motility was assessed by Sperm Class Analyser. Acrosome reaction, apoptosis and intracellular-Ca2+ content were assessed by flow cytometry. We found that TRPV1 mRNA and protein were highly expressed in the testis, in both Sertoli cells and germ-line cells. Moreover, compared to no-gradient controls at 31°C or 37°C (Ctrl 31°C and Ctrl 37°C respectively), sperm migration towards a temperature gradient of 31-37°C (T gradient) in non-capacitated conditions selected a higher number of cells (14,9 ± 4,2×106 cells T gradient vs 5,1± 0,3×106 cells Ctrl 31°C and 5,71±0,74×106 cells Ctrl 37°C; P = 0,039). Capacitation amplified the migrating capability towards the T gradient. Sperms migrated towards the T gradient showed enriched levels of both TRPV1 protein and mRNA. In addition, sperm cells were able to migrate toward a gradient of capsaicin, a specific agonist of TRPV1, whilst capsazepine, a specific agonist of TRPV1, blocked this effect. Finally, capsazepine severely blunted migration towards T gradient without abolishing. These results suggest that TRPV1 may represent a facilitating mediator of sperm thermotaxis.
| S-EPMC5161326 | biostudies-literature
Project description:Mammalian spermatozoa undergo a Ca(2+)-dependent exocytotic event before fertilization which is known as the acrosome reaction. The process of exocytosis in several cell systems is mediated by a protein kinase C (PKC)-catalysed phosphorylation. Addition of phorbol 12-myristate-13-acetate or the membrane-permeant diacylglycerol analogue 1-oleoyl-2-acetylglycerol, which are potent activators of PKC, to bovine spermatozoa resulted in stimulation of the acrosome reaction. This stimulation was inhibited by low concentrations (50% inhibition at 0.7 nM) of the PKC inhibitor staurosporine. PKC specific activity in bovine spermatozoa is extremely low in comparison with other cells; however, it is comparable with the activity found in human spermatozoa. Immunohistochemical analysis using anti-PKC antibodies revealed staining in the equatorial segment, the post-acrosomal region and the upper region of the head. We propose that PKC is involved in the mammalian sperm acrosome reaction.
| S-EPMC1130709 | biostudies-other
Project description:Mammalian spermatozoa employ calcium (Ca2+) and cyclic adenosine monophosphate (cAMP) signaling in generating flagellar beat. However, how sperm direct their movement towards the egg cells has remained elusive. Here we show that the Rho small G protein RAC1 plays an important role in controlling progressive motility, in particular average path velocity and linearity. Upon RAC1 inhibition of wild type sperm with the drug NSC23766, progressive movement is impaired. Moreover, sperm from mice homozygous for the genetically variant t-haplotype region (tw5/tw32), which are sterile, show strongly enhanced RAC1 activity in comparison to wild type (+/+) controls, and quickly become immotile in vitro. Sperm from heterozygous (t/+) males, on the other hand, display intermediate RAC1 activity, impaired progressive motility and transmission ratio distortion (TRD) in favor of t-sperm. We show that t/+-derived sperm consist of two subpopulations, highly progressive and less progressive. The majority of highly progressive sperm carry the t-haplotype, while most less progressive sperm contain the wild type (+) chromosome. Dosage-controlled RAC1 inhibition in t/+ sperm by NSC23766 rescues progressive movement of (+)-sperm in vitro, directly demonstrating that impairment of progressive motility in the latter is caused by enhanced RAC1 activity. The combined data show that RAC1 plays a pivotal role in controlling progressive motility in sperm, and that inappropriate, enhanced or reduced RAC1 activity interferes with sperm progressive movement. Differential RAC1 activity within a sperm population impairs the competitiveness of sperm cells expressing suboptimal RAC1 activity and thus their fertilization success, as demonstrated by t/+-derived sperm. In conjunction with t-haplotype triggered TRD, we propose that Rho GTPase signaling is essential for directing sperm towards the egg cells.
| S-EPMC7861394 | biostudies-literature
Project description:OBJECTIVE:To present an updated, comprehensive review on clinical and pre-clinical studies on agomelatine. METHOD:A MEDLINE, Psycinfo and Web of Science search (1966-May 2009) was performed using the following keywords: agomelatine, melatonin, S20098, efficacy, safety, adverse effect, pharmacokinetic, pharmacodynamic, major depressive disorder, bipolar disorder, Seasonal Affective Disorder (SAD), Alzheimer, ADHD, Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Obsessive-Compulsive Disorder (OCD), anxiety disorders and mood disorder. STUDY COLLECTION AND DATA EXTRACTION: All articles in English identified by the data sources were evaluated. Randomized, controlled clinical trials involving humans were prioritized in the review. The physiological bases of melatonergic transmission were also examined to deepen the clinical comprehension of agomelatine' melatonergic modulation. DATA SYNTHESIS:Agomelatine, a melatonergic analogue drug acting as MT(1)/MT(2) agonist and 5-HT(2C) antagonist, has been reported to be an effective antidepressant therapy. CONCLUSIONS:Although a bias in properly assessing the "sleep core" of depression may still exist with current screening instruments, therefore making difficult to compare agomelatine' efficacy to other antidepressant ones, comparative studies showed agomelatine to be an intriguing option for depression and, potentially, for other therapeutic targets as well.
| S-EPMC3001221 | biostudies-literature
Project description:Genomic imprinting is a complex epigenetic process that contributes substantially to embryogenesis, reproduction, and gametogenesis. Only small fraction of genes within the whole genome undergoes imprinting. Imprinted genes are expressed in a monoallelic parent-of-origin-specific manner, which means that only one of the two inherited alleles is expressed either from the paternal or maternal side. Imprinted genes are typically arranged in clusters controlled by differentially methylated regions or imprinting control regions. Any defect or relaxation in imprinting process can cause loss of imprinting in the key imprinted loci. Loss of imprinting in most cases has a harmful effect on fetal development and can result in neurological, developmental, and metabolic disorders. Since DNA methylation and histone modifications play a key role in the process of imprinting. This review focuses on the role of DNA methylation in imprinting process and describes DNA methylation aberrations in different imprinting disorders.
| S-EPMC5427654 | biostudies-literature
Project description:Being located in a gene desert region on 9q21.11-q21.12, BRAF-activated non-protein coding RNA (BANCR) is an lncRNA with 693 bp length. It has been discovered in 2012 in a research aimed at assessment of gene expression in the melanocytes in association with BRAF mutation. Increasing numbers of studies have determined its importance in the tumorigenesis through affecting cell proliferation, migration, invasion, apoptosis, and epithelial to mesenchymal transition. BANCR exerts its effects via modulating some tumor-related signaling pathways particularly MAPK and other regulatory mechanisms such as sponging miRNAs. BANCR has been up-regulated in endometrial, gastric, breast, melanoma, and retinoblastoma. Conversely, it has been down-regulated in some other cancers such as those originated from lung, bladder, and renal tissues. In some cancer types such as colorectal cancer, hepatocellular carcinoma and papillary thyroid carcinoma, there is no agreement about BANCR expression, necessitating the importance of additional functional studies in these tissues. In the present manuscript, we review the investigations related to BANCR expression changes in cancerous cell lines, clinical samples, and animal models of cancer. We also discuss the outcome of its deregulation in cancer progression, prognosis, and the underlying mechanisms of these observations.
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Project description:Rabbit spermatozoa from the cauda epididymis produced 0.7-0.8nmol of H(2)O(2)/min per 10(8) cells at cell concentrations below 10(7) cells/ml with linear dependence on cell concentration. Above 2 x 10(7) cells/ml, the rate again became linear with cell concentration but decreased to 0.1-0.2nmol/min per 10(8) cells. Spermatozoa treated with amphotericin B, which makes the plasma membrane highly permeable to low-molecular-weight compounds, showed a similar dependence of H(2)O(2) production rate on cell concentration; below 10(7) cells/ml the rate was 0.3-0.4nmol/min per 10(8) cells; above 2 x 10(7) cells/ml, the rate was 0.1-0.2nmol/min per 10(8) cells. Hypo-osmotically treated rabbit epididymal spermatozoa, a preparation useful for studying mitochondrial function in sperm [Keyhani & Storey (1973) Biochim. Biophys. Acta305, 557-565] produced 0.1-0.2nmol/min per 10(8) cells in the absence of added substrates. The dependence of rate on cell concentration was linear from 10(7) to 2.2 x 10(8) cells/ml. This endogenous rate was unaffected by rotenone, but stimulated 4-fold by antimycin A. Addition of the mitochondrial substrates lactate plus malate increased the rate of H(2)O(2) production to 0.3nmol/min per 10(8) cells. The decreased rate of H(2)O(2) production observed with intact sperm at high cell concentrations is attributed to reaction of H(2)O(2) with the cells, possibly with the plasma membrane, which is lost after hypo-osmotic treatment. Rabbit spermatozoa have glutathione peroxidase and glutathione reductase activities, but these seem to play little role in removal of H(2)O(2) generated. The rate at low cell concentration is taken to be the unperturbed rate. The sources of H(2)O(2) production in rabbit spermatozoa have been tentatively resolved into a low-molecular-weight component, lost after amphotericin treatment, a mitochondrial component and a rotenone-insensitive component that has not been identified.
| S-EPMC1163245 | biostudies-other
Project description:In mammals, Ca2+ and HCO3- ions play a critical role in the regulation of sperm function, most likely by regulation of cAMP levels. Mammalian germ cells contain a soluble adenylyl cyclase (sAC) with properties distinct from the well characterized membrane-bound enzymes Here we investigated whether the cyclase expressed in mature spermatozoa has the properties of sAC and whether it is regulated by Ca2+. In addition to an HCO3--dependent activation, the cyclase endogenous to human spermatozoa is stimulated 2- to 3-fold by Ca2+ in a concentration-dependent manner (EC50 approximately 400 nM). In a similar fashion, Ca2+ activates the recombinant rat and human full-length sAC with similar EC50 values. The Ca2+ stimulation was also observed when sAC was activated with HCO3-, was independent of calmodulin, and was associated with an increase in Vmax without changes in Km for ATP-Mg2+. An increase in intracellular Ca2+ by ionophore or by a muscarinic cholinergic receptor agonist increases cAMP in cells transfected with FL-hsAC, but not in mock-transfected cells. Similarly, both Ca2+ and HCO3- stimulate cAMP accumulation in human spermatozoa. These findings provide evidence that human spermatozoa express a cyclase with the properties of sAC and that Ca2+ can substitute for HCO3- in the stimulation of this enzyme, underscoring an important role for sAC in the control of sperm functions.
| S-EPMC196863 | biostudies-literature
Project description:Parasomnias are abnormal behaviors emanating from or associated with sleep. Sleepwalking and related disorders result from an incomplete dissociation of wakefulness from nonrapid eye movement (NREM) sleep. Conditions that provoke repeated cortical arousals, or promote sleep inertia lead to NREM parasomnias by impairing normal arousal mechanisms. Changes in the cyclic alternating pattern, a biomarker of arousal instability in NREM sleep, are noted in sleepwalking disorders. Sleep-related eating disorder (SRED) is characterized by a disruption of the nocturnal fast with episodes of feeding after an arousal from sleep. SRED is often associated with the use of sedative-hypnotic medications; in particular, the widely prescribed benzodiazepine receptor agonists. Recently, compelling evidence suggests that nocturnal eating may in some cases be a nonmotor manifestation of Restless Legs Syndrome (RLS). rapid eye movement (REM) Sleep Behavior Disorder (RBD) is characterized by a loss of REM paralysis leading to potentially injurious dream enactment. The loss of atonia in RBD often predates the development of Parkinson's disease and other disorders of synuclein pathology. Parasomnia behaviors are related to an activation (in NREM parasomnias) or a disinhibition (in RBD) of central pattern generators (CPGs). Initial management should focus on decreasing the potential for sleep-related injury followed by treating comorbid sleep disorders. Clonazepam and melatonin appear to be effective therapies in RBD, whereas paroxetine has been reported effective in some cases of sleep terrors. At this point, pharmacotherapy for other parasomnias is less certain, and further investigations are necessary.
| S-EPMC3480572 | biostudies-other