Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single rat epididymal cell studied under whole cell patch-clamp condition responded to 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP) (500 microM) and to ionomycin (1 microM) by an increase in whole cell conductance. A major part of the stimulated current was carried by Cl-, although a small part was due to nonselective cation current. After elimination of the cation current component by using impermeant cation, the cells revealed different Cl- conductance properties in response to adenosine 3',5'-cyclic monophosphate (cAMP) and ionomycin. The cAMP-stimulated Cl- conductance was independent of time and voltage and showed a linear current-voltage relationship. The anion permselectivity was NO3- > Br- > Cl- approximately I- >> SO(4)2-. The ionomycin-stimulated Cl- conductance showed marked time and voltage dependency. In contrast to the cAMP-induced anion permselectivity, the ionomycin-induced anion permselectivity was I- > Br- approximately NO3- > Cl- >> SO(4)2-. These results indicate that the epididymal epithelial cells exhibit different Cl- conductances sensitive to cAMP and Ca2+. The cAMP-activated conductance has properties resembling the type associated with the cystic fibrosis transmembrane conductance regulator found in cystic fibrosis-affected epithelia. This finding supports the notion that the epididymis is a cystic fibrosis epithelium.
 ...
PMID:Properties of cAMP-dependent and Ca(2+)-dependent whole cell Cl- conductances in rat epididymal cells. 768 72

The majority of men with cystic fibrosis (CF) are infertile due to a bilateral congenital absence of the vas deferens (CBAVD). However, clinically affected CF patients present a spectrum of genital phenotypes ranging from normal fertility to severely impaired spermatogenesis and CBAVD. Recently, it has become apparent that CF can manifest itself as isolated CBAVD in the absence of other clinical symptoms. The present study was undertaken to test the possible involvement of the CF gene in the aetiology of male infertility other than CBAVD. Semen specimens from 127 unrelated healthy males with various diagnoses of reduced sperm quality were screened for a panel of 13 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Fourteen of 80 (17.5%) healthy men with infertility due to reduced sperm quality and 3 of 21 (14.3%) men with azoospermia had at least one CF mutation (one azoospermic male was a compound heterozygote). The frequency of mutations in our sample of infertile males was significantly higher than the expected CF carrier frequency in the local population (P = 0.00139). No mutations were found in a control group of 26 individuals with normal semen parameters. This increased frequency of CF mutations in healthy men with reduced sperm quality and in men with azoospermia without CBAVD suggests that the CFTR protein may be involved in the process of spermatogenesis or sperm maturation apart from playing a critical role in the development of the epididymal glands and the vas deferens.
 ...
PMID:Cystic fibrosis mutation screening in healthy men with reduced sperm quality. 867 Dec 56

Electrogenic chloride and bicarbonate secretion by cultured rat epididymal epithelia was studied using the short-circuit current (ISC) technique. When incubated in normal solution, 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (cpt-cAMP) caused a rise in the ISC, which was attributable to Cl- and HCO3- secretion. Cl- secretion was found to contribute to the initial transient phase, whereas HCO3- secretion contributed to the sustained phase of the response. HCO3- secretion involves a basolaterally placed Na(+)-H+ exchanger and apical anion channel, most probably the cystic fibrosis transmembrane conductance regulator (CFTR). There is also evidence that an apical electrogenic Na(+)-HCO3- cotransporter is involved in HCO3- exit. CFTR accounted for 70% of HCO3- secretion, while the Na(+)-HCO3- cotransporter accounted for 30%. The possibility that the cotransporter may serve as an alternative pathway for HCO3- secretion in cystic fibrosis is discussed.
 ...
PMID:Evidence for independent Cl- and HCO3- secretion and involvement of an apical Na(+)-HCO3- cotransporter in cultured rat epididymal epithelia. 873 84

The splicing variant, 5T allele, in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was shown to be associated with partial penetrance of the clinical expression. This splicing variant leads to two possible transcripts: one normal and the other aberrantly spliced that lacks exon 9. The aim of this study was to analyze the molecular basis of the partial penetrance in individuals carrying the 5T allele. We analyzed the level of the correctly spliced RNA transcribed from the 5T allele in nasal and epididymal epithelium and correlated it with disease expression. Semiquantitative nondifferential reverse-transcriptase-PCR showed a considerable variability (6%-37%) in the total level of correctly spliced RNA transcribed from the 5T allele in nasal epithelium from 11 patients. A significant nonlinear correlation (r = .82, P = .002) between the level of the normal CFTR transcripts and the severity of lung disease was shown. No individuals with normal lung function and minimal or no lung disease (FEV1 >80% predicted) had <25% of normal transcripts, and individuals with <15% of normal transcripts did not have FEV1 >80%. The level of normal transcripts in epididymal epithelial cells from four infertile males with congenital bilateral absence of the vas deferens was low (6%-24%). In infertile males with normal lung function the level of correctly spliced transcripts in the nasal epithelium was higher than the level in the epididymal epithelium. These results indicate that there is variability in the efficiency of the splicing mechanism, among different individuals and between different organs of the same individual. This variability provides the molecular basis of the partial penetrance of cystic fibrosis disease in patients carrying the 5T allele.
 ...
PMID:The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. 898 51

The effect of genistein on anion secretion via cystic fibrosis transmembrane conductance regulator (CFTR) in cultured rat cauda epididymal epithelia was studied by short-circuit current (Isc) technique. Genistein added apically stimulated a concentration-dependent rise in Isc due to Cl(-) and HCO(3)(-) secretion. The genistein-induced Isc was observed in basolaterally permeabilized monolayers, suggesting that the Isc response was mediated by the apical anion channel. The response could be blocked by the nonspecific Cl(-) channel blocker, diphenylamine-2-carboxylate (DPC), but not by the Ca(2+)-activated Cl(-) channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Genistein did not increase intracellular cAMP, but H-89, a protein kinase A inhibitor, completely abolished the Isc response to genistein. Moreover, pretreatment of the tissues with MDL-12330A, an adenylate cyclase inhibitor, markedly attenuated the Isc response to genistein, but the response was restored upon the addition of exogenous cAMP. Ca(2+), protein kinase C, tyrosine kinase, and protein phosphatase signalling pathways were not involved in the action of genistein. It is speculated that genistein stimulates anion secretion by direct interaction with CFTR. This requires a low level of phosphorylation of CFTR by basal protein kinase A activity. It is suggested that genistein may provide therapeutic benefit to male infertility associated with cystic fibrosis.
 ...
PMID:Activation of cystic fibrosis transmembrane conductance regulator in rat epididymal epithelium by genistein. 1061 Oct 78

Secretion of electrolytes and water by the epididymal epithelium is important in the formation of an optimal fluid environment for sperm maturation and storage. Recently, evidence has been obtained that anion/fluid secretion by the epididymis is subject to control by local humoral factors, among which the angiotensins play a significant role. This assertion is based on the morphological localization of various components of a local renin-angiotensin system (RAS) in the rat epididymis and the functional studies of angiotensins and their antagonists on anion secretion in cultured rat epididymal epithelia. More recent study has indicated that the effects of angiotensin II and other vasoactive peptides on anion secretion are mediated through an increase in prostaglandin formation. The pathway of synthesis involves the PLA2-coupled receptor mediated breakdown of membrane phospholipids to arachidonic acid followed by conversion of arachidonic acid into the prostanoids by cyclooxygenases and other enzymes. The newly formed PGE2 then diffuses out of the cells and acts on the EP2/4 receptors on the same or adjacent cells to increase intracellular cAMP. Accordingly, the pathways of activation by the paracrine factors all converge on the cystic fibrosis transmembrane conductance regulator (CFTR) as the final common effector in secretion. Studies on the biochemical pathways of paracrine control of fluid secretion may provide insight into the causes of epididymal irregularities in some forms of male infertility.
 ...
PMID:The role of local angiotensins and prostaglandins in the control of anion secretion by the rat epididymis. 1064 62

The pathogenesis of the aberrant development of the male genital tract (epididymis, vas deferens and seminal vesicles) seen in patients with congenital bilateral absence of the vas deferens (CBAVD) is still unclear. Since men with CBAVD carry mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), it is likely that CFTR mRNA of the translated protein plays a major role in the pathogenesis of CBAVD. The aim of this study was to compare the pattern of expression of CFTR mRNA in epididymides of men with CBAVD and other types of obstruction (post-vasectomy and post-inflammatory) with that of normal non-obstructed adult epididymis. Epididymal biopsies were obtained at the time of microsurgical epididymal sperm aspiration procedures or during vaso-epididymostomy reanastomosis. A normal epididymis was obtained from an orchiectomy specimen. After standard processing for in situ hybridization, tissue sections were hybridized with CFTR gene-probe labelled by incorporation of digoxigenin-dUTP. After hybridization the signal was detected by an alkaline phosphatase-tagged antidigoxigenin antibody. CFTR mRNA was clearly identified in the columnar epithelium of the normal adult epididymis and vas deferens and the signal intensity was greatest in the most proximal regions of the caput epididymis. In contrast, men with genital tract obstructions due to CBAVD or post-vasectomy or post-inflammatory obstructions, had sloughing of the epithelial cells lining the lumen and as a consequence CFTR mRNA expression was lacking. In one subject (post-vasectomy obstruction), some residual caput epididymal epithelium was preserved and CFTR mRNA was detected. The abundant CFTR mRNA expression in the proximal caput of the epididymis and vas deferens under normal conditions strongly favours the hypothesis of an early obstructive process in the pathogenesis of CBAVD. The absent or severely reduced activity of CFTR protein affects the ionic exchange and fluid content within the epididymal lumen and this, in turn, can lead to excessive viscosity of the epididymal fluid, sloughing of epithelial cells expressing CFTR and further reduction in the amount of CFTR activity. As a consequence, variable segments of the epididymis and the vas deferens may be blocked and progressively obliterated. The epididymal lumen obstruction could also sustain the anatomical defects by not allowing testosterone to exert a local action on the mesonephric duct.
 ...
PMID:Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA in normal and pathological adult human epididymis. 1064 85

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are a relatively frequent cause of male infertility. Depending on their molecular consequences, CFTR mutations may either result in typical cystic fibrosis (CF), one of the most common autosomal recessive disorders, which is characterized by chronic lung disease, pancreatic exocrine insufficiency, an increase in the concentration of sweat electrolytes and male infertility, due to obstructive azoospermia, or in atypical (often monosymptomatic) forms of CF such as congenital absence of the vas deferens (bi- or unilateral), bilateral ejaculatory duct obstruction or bilateral obstructions within the epididymides. All males with idiopathic obstructive azoospermia bear an increased risk for CF offspring. Couples requesting microsurgical epididymal sperm aspiration and in vitro fertilization, e.g. intracytoplasmic sperm injection, should be offered genetic counselling and molecular genetic analysis of the CFTR gene, if male infertility due to obstructive azoospermia is the underlying cause.
 ...
PMID:CFTR gene mutations and male infertility. 1075 89

The cystic fibrosis transmembrane conductance regulator (CFTR) or the small conductance cAMP-activated chloride channel encoded by the CFTR gene has been shown to play an important role in the formation of the epididymal fluid microenvironment. Mutation of the gene has led to widespread effects on male reproduction. Like other ion channels, CFTR is amenable to pharmacological intervention. Blocking CFTR in the epididymis could in principle lead to disruption of the epididymal fluid environment. We report for the first time two indazole compounds: lonidamine and 1-(2, 4-dichlorobenzyl)-indazole-3-acrylic acid (AF2785) are potent blockers of CFTR in the epididymis. When added to the external solution under whole-cell patch clamp conditions, AF2785 and lonidamine inhibited the cAMP-activated chloride current in rat epididymal cells with apparent IC(50) values of 170.6 and 631.5 microM, respectively; by comparison the IC(50) value for diphenylamine-2-carboxylate, a well-known chloride channel blocker was 1294 microM. In cultured rat epididymal epithelia mounted in a Ussing chamber, AF2785 and lonidamine inhibited the cAMP-stimulated short-circuit current (a measure of chloride secretion) when added to the apical bathing solution with potency greater than any known chloride channel studied. It is proposed that in view of the important role CFTR plays in male reproduction, further study with these and other new indazole compounds for their CFTR blocking actions can provide a new avenue of research into the development of novel male contraceptives.
 ...
PMID:Lonidamine and analogue AF2785 block the cyclic adenosine 3', 5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis. 1095 28

The cystic fibrosis transmembrane conductance regulator (CFTR) or the small conductance cAMP-activated chloride channel encoded by the CFTR gene has been shown to play an important role in the formation of the epididymal fluid microenvironment. Recent work in our laboratory has shown that this protein is also expressed by developing germ cells indicating a role of this protein in spermatogenesis. In view of the fact that the CFTR gene has a far reaching and widespread effect on human reproduction, understanding the role of CFTR in the male reproductive tissues and its intervention by pharmacological agents can open a new avenue of research into the development of novel male contraceptives.
 ...
PMID:Interference with the formation of the epididymal microenvironment--a new strategy for male contraception? 1122 36


1 2 3 Next >>