scholarly journals Characterization of gametogenetin 1 (GGN1) and its potential role in male fertility through the interaction with the ion channel regulator, cysteine-rich secretory protein 2 (CRISP2) in the sperm tail

Reproduction ◽  
2008 ◽  
Vol 135 (6) ◽  
pp. 751-759 ◽  
Author(s):  
Duangporn Jamsai ◽  
Deborah M Bianco ◽  
Stephanie J Smith ◽  
Donna J Merriner ◽  
Jennifer D Ly-Huynh ◽  
...  
Keyword(s):  
Ion Channel ◽  
Male Fertility ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Regulatory Region ◽  
Secretory Protein ◽  
Sperm Tail ◽  
Testis Cdna ◽  
Principal Piece ◽  
Pachytene Spermatocytes

Cysteine-rich secretory protein 2 (CRISP2) is a testis-enriched protein localized to the sperm acrosome and tail. CRISP2 has been proposed to play a critical role in spermatogenesis and male fertility, although the precise function(s) of CRISP2 remains to be determined. Recent data have shown that the CRISP domain of the mouse CRISP2 has the ability to regulate Ca2+flow through ryanodine receptors (RyR) and to bind to MAP kinase kinase kinase 11 (MAP3K11). To further define the biochemical pathways within which CRISP2 is involved, we screened an adult mouse testis cDNA library using a yeast two-hybrid assay to identify CRISP2 interacting partners. One of the most frequently identified CRISP2-binding proteins was gametogenetin 1 (GGN1). Interactions occur between the ion channel regulatory region within the CRISP2 CRISP domain and the carboxyl-most 158 amino acids of GGN1. CRISP2 does not bind to the GGN2 or GGN3 isoforms. Furthermore, we showed thatGgn1is a testis-enriched mRNA and the protein first appeared in late pachytene spermatocytes and was up-regulated in round spermatids before being incorporated into the principal piece of the sperm tail where it co-localized with CRISP2. These data along with data on RyR and MAP3K11 binding define the CRISP2 CRISP domain as a protein interaction motif and suggest a role for the GGN1–CRISP2 complex in sperm tail development and/or motility.

scholarly journals Mitochondrial Contributions in the Genesis of Delayed Afterdepolarizations in Ventricular Myocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Vikas Pandey ◽  
Lai-Hua Xie ◽  
Zhilin Qu ◽  
Zhen Song
Keyword(s):  
Signaling Pathways ◽  
Energy Demand ◽  
Mitochondrial Permeability Transition ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Mitochondrial Depolarization ◽  
Delayed Afterdepolarizations ◽  
Camkii Activation

Mitochondria fulfill the cell’s energy demand and affect the intracellular calcium (Ca2+) dynamics via direct Ca2+ exchange, the redox effect of reactive oxygen species (ROS) on Ca2+ handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca2+ signaling pathways, ROS, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms. Here, we use a recently developed spatiotemporal ventricular myocyte computer model, which consists of a 3-dimensional network of Ca2+ release units (CRUs) intertwined with mitochondria and integrates mitochondrial Ca2+ signaling and other complex signaling pathways, to study the mitochondrial regulation of DADs. With a systematic investigation of the synergistic or competing factors that affect the occurrence of Ca2+ waves and DADs during mitochondrial depolarization, we find that the direct redox effect of ROS on ryanodine receptors (RyRs) plays a critical role in promoting Ca2+ waves and DADs under the acute effect of mitochondrial depolarization. Furthermore, the upregulation of mitochondrial Ca2+ uniporter can promote DADs through Ca2+-dependent opening of mitochondrial permeability transition pores (mPTPs). Also, due to much slower dynamics than Ca2+ cycling and ROS, oxidized CaMKII activation and the cytosolic ATP do not appear to significantly impact the genesis of DADs during the acute phase of mitochondrial depolarization. However, under chronic conditions, ATP depletion suppresses and enhanced CaMKII activation promotes Ca2+ waves and DADs.

The Anatomy, Movement and Functions of Human Sperm Tail: An Evolving Mystery

2020 ◽  
Author(s):  
Naina Kumar ◽  
Amit Kant Singh
Keyword(s):  
Sperm Motility ◽  
Male Fertility ◽  
English Language ◽  
Complex Structure ◽  
Relevant Literature ◽  
Human Sperm ◽  
Small Subunit ◽  
Sperm Tail ◽  
Complex Anatomy ◽  
Tail Movement

Abstract Sperms have attracted the attention of many researchers since it was discovered by Antonie van Leeuwenhoek in 1677. Though a small cell, its every part has complex structure and a different function to play in carrying life further. Sperm tail is the most complicated structure with more than 1000 proteins involved in its functioning. With advent of advanced three-dimensional microscopes, many studies are still undergoing to understand the exact mechanism of sperm tail movement. Most recent studies have shown that sperms move by spinning rather than swimming. Furthermore, each small subunit of tail including axonemal and peri-axonemal structures play essential roles in sperm motility, capacitation, hyperactivation, fertilization. Methodology: Relevant literature (from 1982 till 2020) on sperm tail anatomy, movement and functions were searched from various English language full length and review articles using PUBMED, SCOPUS or Google database. Conclusion: There is still a lot needed to be discovered about human sperm tail movement and its role in male fertility. Sperm tail has a complex anatomy with surrounding axoneme having 9+2 microtubules (9 outer doublet and one central doublet) arrangement along its entire length and additional peri-axonemal structures that all contribute in sperm motility and fertilization. In future various sperm tail proteins and its subunits can be used as markers of male fertility.

scholarly journals RNF216 is essential for spermatogenesis and male fertility†

2019 ◽  
Vol 100 (5) ◽  
pp. 1132-1134 ◽  
Author(s):  
Ashley F Melnick ◽  
Yuen Gao ◽  
Jiali Liu ◽  
Deqiang Ding ◽  
Alicia Predom ◽  
...  
Keyword(s):  
Male Fertility ◽  
Mammalian Species ◽  
Critical Role ◽  
Ring Finger ◽  
Gonadal Development ◽  
Cellular Protein ◽  
Ring Finger Protein ◽  
Targeted Deletion ◽  
Finger Protein ◽  
Essential Function

Abstract Ring finger protein 216 (RNF216) belongs to the RING family of E3 ubiquitin ligases that are involved in cellular protein degradation. Mutations in human Rnf216 gene have been identified in Gordon Holmes syndrome, which is defined by ataxia, dementia, and hypogonadotropism. However, the gene function of Rnf216 in mammalian species remains unknown. Here, we show that targeted deletion of Rnf216 in mice results in disruption in spermatogenesis and male infertility. RNF216 is not required for female fertility. These findings reveal an essential function of RNF216 in spermatogenesis and male fertility and suggest a critical role for RNF216 in human gonadal development.

An epididymis-specific secretory protein Clpsl2 critically regulates sperm motility, acrosomal integrity, and male fertility

2018 ◽  
Vol 119 (6) ◽  
pp. 4760-4774 ◽  
Author(s):  
Xiaosheng Lu ◽  
Fei Ding ◽  
Zizhen Lian ◽  
Lei Chen ◽  
Zuowu Cao ◽  
...  
Keyword(s):  
Sperm Motility ◽  
Male Fertility ◽  
Secretory Protein ◽  
Acrosomal Integrity

249. Fibroblast growth factor receptor-1 (FGFR-1) is essential for spermiogenesis, capacitation and male fertility

2005 ◽  
Vol 17 (9) ◽  
pp. 99
Author(s):  
L. M. Cotton ◽  
G. M. Gibbs ◽  
D. M. De Kretser ◽  
M. K. O'Bryan
Keyword(s):  
Transgenic Mice ◽  
Male Fertility ◽  
Transgene Expression ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Sperm Tail ◽  
Expression Levels ◽  
Over Expression ◽  
Sperm Development

Male infertility is often a result of irregular sperm development/function. The identification of snt-2 (Suc-1 associated Neurotrophic Factor Target 2) and Fgfr-1 to the sperm tail, lead to the hypothesis that Fgf signalling through snt-2 is involved in sperm tail development/function. To test this hypothesis, transgenic mice carrying a dominant-negative variant of Fgfr-1, driven by the protamine 1 promoter (haploid specific) were created. Breeding experiments confirmed male fertility; however, one line was significantly sub-fertile and demonstrated a significantly reduced daily sperm production (DSP, 30%↓). Transgene expression levels were up to 70 times above native mRNA levels in wt mice; however, there was a concurrent upregulation of the native receptor in transgenic mice, resulting in only a 6× over-expression in transgenic:native mRNA. To increase transgene expression, independent lines were crossed (double heterozygous, DH). DH transgene expression levels were up to 120 times above the native mRNA in wild type mice, resulting in a 20× over-expression in transgenic:native mRNA. Breeding experiments showed males from 1 cross were significantly subfertile with DSPs further reduced (41%↓). Collectively this data shows Fgfr-1 signalling is required for quantitatively normal spermiogenesis. Given the millions of sperm that mice produce, a 40%↓ in DSP is unlikely to be responsible for the sub-fertility observed i.e. 2 v. 9 pups/litter. Therefore, a disruption of Fgfr-1 signalling may also induce a post-testicular phenotype. Western blot analysis, using tyrosine phosphorylation as a surrogate marker of sperm capacitation, showed transgenic mice had a significantly attenuated ability to initiate capacitation. As capacitation is an absolute requirement for fertilisation, the absence of capacitating capability is probably the major contributor to the sub-fertility seen in the transgenic mice. This research demonstrates for the first time that the Fgfr-1 signalling cascade is one of several pathways associated with sperm development and function.

scholarly journals Phosphorylation-Dependent Regulation of Ryanodine Receptors

2001 ◽  
Vol 153 (4) ◽  
pp. 699-708 ◽  
Author(s):  
Steven O. Marx ◽  
Steven Reiken ◽  
Yuji Hisamatsu ◽  
Marta Gaburjakova ◽  
Jana Gaburjakova ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Rapid Identification ◽  
Calcium Release Channels ◽  
Macromolecular Complexes ◽  
Protein Binding Sites ◽  
Skeletal Muscle Contraction

Ryanodine receptors (RyRs), intracellular calcium release channels required for cardiac and skeletal muscle contraction, are macromolecular complexes that include kinases and phosphatases. Phosphorylation/dephosphorylation plays a key role in regulating the function of many ion channels, including RyRs. However, the mechanism by which kinases and phosphatases are targeted to ion channels is not well understood. We have identified a novel mechanism involved in the formation of ion channel macromolecular complexes: kinase and phosphatase targeting proteins binding to ion channels via leucine/isoleucine zipper (LZ) motifs. Activation of kinases and phosphatases bound to RyR2 via LZs regulates phosphorylation of the channel, and disruption of kinase binding via LZ motifs prevents phosphorylation of RyR2. Elucidation of this new role for LZs in ion channel macromolecular complexes now permits: (a) rapid mapping of kinase and phosphatase targeting protein binding sites on ion channels; (b) predicting which kinases and phosphatases are likely to regulate a given ion channel; (c) rapid identification of novel kinase and phosphatase targeting proteins; and (d) tools for dissecting the role of kinases and phosphatases as modulators of ion channel function.

scholarly journals L-type calcium channels and MAP kinase contribute to thyrotropin-releasing hormone-induced depolarization in thalamic paraventricular nucleus neurons

2016 ◽  
Vol 310 (11) ◽  
pp. R1120-R1127 ◽  
Author(s):  
Miloslav Kolaj ◽  
Li Zhang ◽  
Leo P. Renaud
Keyword(s):  
Transient Receptor Potential ◽  
Cannabinoid Receptor ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Receptor Potential ◽  
Thyrotropin Releasing Hormone ◽  
Induced Response ◽  
Inward Current ◽  
Releasing Hormone ◽  
Intracellular Ca

In rat paraventricular thalamic nucleus (PVT) neurons, activation of thyrotropin-releasing hormone (TRH) receptors enhances neuronal excitability via concurrent decrease in a G protein-coupled inwardly rectifying K (GIRK)-like conductance and opening of a cannabinoid receptor-sensitive transient receptor potential canonical (TRPC)-like conductance. Here, we investigated the calcium (Ca2+) contribution to the components of this TRH-induced response. TRH-induced membrane depolarization was reduced in the presence of intracellular BAPTA, also in media containing nominally zero [Ca2+]o, suggesting a critical role for both intracellular Ca2+ release and Ca2+ influx. TRH-induced inward current was unchanged by T-type Ca2+ channel blockade, but was decreased by blockade of high-voltage-activated Ca2+ channels (HVACCs). Both the pharmacologically isolated GIRK-like and the TRPC-like components of the TRH-induced response were decreased by nifedipine and increased by BayK8644, implying Ca2+ influx via L-type Ca2+ channels. Only the TRPC-like conductance was reduced by either thapsigargin or dantrolene, suggesting a role for ryanodine receptors and Ca2+-induced Ca2+ release in this component of the TRH-induced response. In pituitary and other cell lines, TRH stimulates MAPK. In PVT neurons, only the GIRK-like component of the TRH-induced current was selectively decreased in the presence of PD98059, a MAPK inhibitor. Collectively, the data imply that TRH-induced depolarization and inward current in PVT neurons involve both a dependency on extracellular Ca2+ influx via opening of L-type Ca2+ channels, a sensitivity of a TRPC-like component to intracellular Ca2+ release via ryanodine channels, and a modulation by MAPK of a GIRK-like conductance component.

A probable role of dihydropyridine receptors in repression of Ca2+ sparks demonstrated in cultured mammalian muscle

2006 ◽  
Vol 290 (2) ◽  
pp. C539-C553 ◽  
Author(s):  
Jingsong Zhou ◽  
Jianxun Yi ◽  
Leandro Royer ◽  
Bradley S. Launikonis ◽  
Adom González ◽  
...  
Keyword(s):  
Ryanodine Receptors ◽  
Critical Role ◽  
Primary Cultures ◽  
Inhibitory Effect ◽  
Wild Type ◽  
Dihydropyridine Receptors ◽  
Skeletal Muscle Contraction ◽  
Probable Role ◽  
Emission Ratios

To activate skeletal muscle contraction, action potentials must be sensed by dihydropyridine receptors (DHPRs) in the T tubule, which signal the Ca2+ release channels or ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) to open. We demonstrate here an inhibitory effect of the T tubule on the production of sparks of Ca2+ release. Murine primary cultures were confocally imaged for Ca2+ detection and T tubule visualization. After 72 h of differentiation, T tubules extended from the periphery for less than one-third of the myotube radius. Spontaneous Ca2+ sparks were found away from the region of cells where tubules were found. Immunostaining showed RyR1 and RyR3 isoforms in all areas, implying inhibition of both isoforms by a T tubule component. To test for a role of DHPRs in this inhibition, we imaged myotubes from dysgenic mice ( mdg) that lack DHPRs. These exhibited T tubule development similar to that of normal myotubes, but produced few sparks, even in regions where tubules were absent. To increase spark frequency, a high-Ca2+ saline with 1 mM caffeine was used. Wild-type cells in this saline plus 50 μM nifedipine retained the topographic suppression pattern of sparks, but dysgenic cells in high-Ca2+ saline did not. Shifted excitation and emission ratios of indo-1 in the cytosol or mag-indo-1 in the SR were used to image [Ca2+] in these compartments. Under the conditions of interest, wild-type and mdg cells had similar levels of free [Ca2+] in cytosol and SR. These data suggest that DHPRs play a critical role in reducing the rate of spontaneous opening of Ca2+ release channels and/or their susceptibility to Ca2+-induced activation, thereby suppressing the production of Ca2+ sparks.

Pregnancy following discontinuation of a calcium channel blocker in the male partner

1995 ◽  
Vol 10 (3) ◽  
pp. 599-606 ◽  
Author(s):  
Avner Hershlag ◽  
George W. Cooper ◽  
Susan Benoff
Keyword(s):  
Ion Channel ◽  
Calcium Ion ◽  
Male Fertility ◽  
Channel Blocker ◽  
Male Partner ◽  
Channel Blockers ◽  
Ligand Receptors ◽  
Fertility Potential ◽  
Intra Uterine Insemination

Abstract The fertility potential of human sperm populations can be assessed by the presence of head-directed mannose ligand receptors (mannose-specific lectin) and the occurrence of spontaneous acrosome reactions after incubation under capacitating conditions in vitro. We have reported previously on the interaction between anti-hypertensive medications and their effects on these parameters of male fertility potential. In this report we document the effects of cessation of calcium ion channel blocker medication on male fertility. Motile spermatozoa from a 30 year old infertile patient on a calcium ion channel blocker as anti-hypertensive treatment had subnormal expression of mannose-specific lectin and did not exhibit spontaneous acrosome reactions. Three months following discontinuation of the medications, complete recovery of both the expression of head-directed mannose ligand receptors and the acrosome reaction was documented, though sperm motility and morphology remained unchanged. The couple had 2 years of infertility and previously failed to conceive through seven cycles of Pergonal/intra-uterine insemination. Conception occurred on the second Pergonal/intra-uterine insemination cycle after the husband discontinued calcium ion channel blocker medication. Calcium ion channel blockers may adversely affect sperm fertilizing potential. Discontinuation of such medications enhances the chances for conception.

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