UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CRF is produced in the Leydig cells and acts as a negative autocrine regulator of Leydig cell function. To clarify the hormonal control of CRF secretion by Leydig cells, we evaluated the participation of serotonin (5HT) and serotonin agonists in the release of CRF from Leydig cells and their effects on hCG-induced cAMP generation and steroidogenesis. Serotonin stimulated CRF secretion up to 4-fold above basal levels and inhibited basal and hCG-stimulated cAMP generation and testosterone production (ID50, 1 nM). The inhibitory action of 5HT was prevented by a CRF antibody and the alpha-helical CRF-(9-41) antagonist. The selective 5HT2 receptor agonist (+-)1-[2,5-dimethoxy-4-iodophyryl]2-amino propane hydrochloride (DOI) also stimulated CRF secretion and inhibited hCG-stimulated cAMP generation and testosterone production to control levels (ID50, 7 microM). Serotonergic 5HT1A, 5HT1B/1C, 5HT1D, and 5HT3/5HT2 agonists were less effective inhibitors of hCG-stimulated cAMP and testosterone production, while agonists for the 5HT3 receptor had no effect. [125I]DOI binding studies in Leydig cells demonstrated two sets of receptors with Kd values in the nanomolar and micromolar range, with low and high capacities, respectively. The low affinity site differed from that of brain receptors (Kd, 4.2 nM) and displayed higher binding capacity (50-fold). The selective 5HT2 receptor antagonist ketanserin prevented CRF stimulation and blocked the inhibitory actions of 5HT and DOI, while the alpha 1-adrenergic antagonist prazosin had no effect. Also, treatment of cells with ketanserin increased sensitivity to hCG and raised maximal cAMP and testosterone production. 5HT was a more effective stimulus than hCG in stimulating CRF secretion, and gonadotropin-induced CRF release was inhibited by ketanserin. Inhibitory effects of exogenous CRF were demonstrable after blockade of 5HT action by ketanserin. The inhibitory actions of 5HT were unaffected by pertussis and cholera toxins and were reversed by the addition of 8-bromo-cAMP. These results demonstrate that 5HT acts on 5HT2 receptors in Leydig cells that are distinct from those in the brain to stimulate CRF secretion through a pertussis toxin-insensitive G-protein. This action of 5HT is predominantly mediated by the low affinity 5HT2-binding site and requires full occupancy for maximal CRF stimulation, indicating the absence of spare receptors. 5HT-stimulated CRF inhibits basal and hCG-induced cAMP generation and steroidogenesis. Furthermore, 5HT mediates the stimulatory action of LH/hCG on CRF secretion from Leydig cells and, thus, participates in a negative autoregulatory loop to limit the testosterone response to the gonadotropic stimulus.
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PMID:Regulation of corticotropin-releasing factor secretion from Leydig cells by serotonin. 131 25

We have recently demonstrated the presence in the rat Leydig cells of a corticotropin releasing factor (CRF) receptor and an inhibitory action of the peptide on human chorionic gonadotropin (hCG)-induced cAMP generation and steroidogenesis. The inhibitory action of CRF was unaffected by pertussis toxin and was completely reversed by 8-bromo-cAMP (Ulisse, S., Fabbri, A., and Dufau, M. L. (1989) J. Biol. Chem. 264, 2156-2163). In this study, we have evaluated the participation of protein kinase C in CRF action in the Leydig cells and the level of the gonadotropin signal pathway affected by CRF. Binding of 125I-labeled ovine CRF to Leydig cell membranes was reduced by GTP and guanyl-5'-yl imidodiphosphate (Gpp(NH)p), in a dose-dependent manner. Phorbol 12-myristate 13-acetate, like CRF, caused time-dependent inhibition of hCG-induced cAMP generation and steroidogenesis. This inhibitory action was reversed by 8-bromo-cAMP. Both CRF and 12-O-tetradecanoylphorbol-13-acetate did not affect 125I-hCG binding. No additive effects of CRF and the phorbol ester were observed in these studies. CRF caused a rapid translocation of protein kinase C in Leydig cells. Preincubation of cells with protein kinase C inhibitors or TPA-induced depletion of protein kinase C prevented the inhibitory actions of CRF and TPA. CRF and TPA were able to inhibit the stimulation of cAMP and testosterone production by cholera toxin and forskolin. Adenylate cyclase stimulation by Gpp(NH)p, luteinizing hormone + Gpp(NH)p, and NaF in crude membranes or by forskolin and manganese in solubilized membranes, prepared from CRF- and TPA-treated cells, was also markedly inhibited. We conclude that CRF receptors interact with a pertussis toxin-insensitive G protein (possibly Gp) in the Leydig cell and that the inhibitory action of CRF on Leydig cell function is exerted mainly on the catalytic subunit of adenylate cyclase through a direct or indirect action of protein kinase C.
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PMID:A novel mechanism of action of corticotropin releasing factor in rat Leydig cells. 215 73

In addition to well known direct stimulatory and potentiatory actions of forskolin, we have previously reported that low doses of this diterpene (10(-9), 10(-12) M) markedly inhibit the production of cAMP and testosterone in rat Leydig cells through a pertussis toxin sensitive G-protein (A. Khanum and M. L. Dufau, J. Biol. Chem. 261, 1986). A different type of inhibitory effect of forskolin is described in this study. Forskolin (10(-5) M) markedly stimulates basal adenylate cyclase activity (about 200%) in rat Leydig cell membranes and potentiates the stimulatory effect of gonadotropin (10(-9), 10(-7) M) on adenylate cyclase in presence or in absence of GTP (10(-5) M). Similarly a time-dependent stimulation of forskolin (10(-5) M) alone is noted on all cAMP pools and testosterone production. Using a supramaximal steroidogenic dose of hCG (0.26 nM) or choleragen (0.1 microM), forskolin potentiates the gonadotrophin and toxin-induced responses of all cAMP pools significantly while inhibiting testosterone production. Moreover, forskolin also inhibits 8-Bromo-cAMP stimulated steroidogenesis. In contrast, pregnenolone synthesis was not altered by the diterpene. We have demonstrated in this study that the inhibitory effect of high doses of forskolin on steroidogenesis is distal to cAMP generation, and resulted from a steroidogenic block residing beyond pregnenolone synthesis.
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PMID:A cAMP independent inhibitory action of high doses of forskolin in rat Leydig cells. 217 27

Rat Leydig cells possess functional high affinity receptors for corticotropin-releasing factor (CRF). CRF inhibited human chorionic gonadotropin (hCG)-induced androgen production in cultured fetal and adult Leydig cells in a dose-dependent manner, but it had no effect on basal testosterone secretion. Comparable inhibitory effects of CRF were observed in the presence or absence of 3-isobutyl-1-methylxanthine. CRF treatment caused a marked reduction of steroid precursors of the androgen pathway (from pregnenolone to testosterone) during gonadotropin stimulation, but it did not influence their basal levels. The inhibitory action of CRF on hCG-induced steroidogenesis was fully reversed by 8-bromo-cAMP but was not affected by pertussis toxin. The action of CRF was rapid; and it was blocked by coincubation with anti-CRF antibody. CRF caused no changes in hCG binding to Leydig cells, and in contrast to other target tissues, CRF did not stimulate cAMP production, indicating that CRF receptors are not coupled to Gs in Leydig cells. These studies have demonstrated that CRF-induced inhibition of the acute steroidogenic action of hCG is exerted at sites related to receptor/cyclase coupling or cAMP formation. The inhibitory effects of CRF in the Leydig cell do not occur through the Gi unit of adenylate cyclase, but could involve pertussis toxin-insensitive G protein(s). These observations demonstrate that CRF has a novel and potent antireproductive effect at the testicular level. Since CRF is synthesized in the testis and is present in Leydig cells, it is likely that locally produced CRF could exert negative autocrine modulation on the stimulatory action of luteinizing hormone on Leydig cell function.
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PMID:Corticotropin-releasing factor receptors and actions in rat Leydig cells. 246 87

To elucidate further the seminiferous tubule-Leydig cell interaction we studied the effect of spent medium from 20 h rat seminiferous tubule cultures (STCM) on cyclic adenosine monophosphate (cAMP) and testosterone (T) production of Percoll-purified Leydig cells. 8% of STCM inhibited the human chorionic gonadotropin (hCG)-stimulated cAMP production by 30% in a 3 h, and 33% of STCm by 60% in a 20 h incubation. Likewise, a 40% decrease was found in the presence of 8% of STCM in the hCG-stimulated T production in a 3 h incubation. A similar inhibitory activity could be demonstrated in steroid-free rat interstitial fluid. STCM did not affect the viability of the Leydig cells (90-95% after a 20 h incubation) as judged by trypan blue exclusion and the adenosine triphosphate (ATP) content of the cells. Heating (80 degrees C for 10 min) abolished the inhibiting activity, and fractionation with Millipore Ultrafree filters showed that the inhibiting factor had an Mr of 30,000-100,000. When media from different stages of the seminiferous epithelial cycle were analyzed, only stages IX-I showed inhibition of T production (P less than 0.05). The cAMP production inhibiting activity was present in all stages, but stages IX-I showed significantly (P less than 0.05) greater inhibition than stages II-VI. STCM (16%) also inhibited cholera toxin- and forskolin-stimulated cAMP formation (approximately 50 and 60%, respectively; P less than 0.01), and the inhibitory activity persisted after a 3 h preincubation of Leydig cells with 100 micrograms/l pertussis toxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A rat seminiferous epithelial factor that inhibits Leydig cell cAMP and testosterone production: mechanism of action, stage-specific secretion, and partial characterization. 255 Feb 94

delta 9-Tetrahydrocannabinol (THC), the major psychoactive component in marihuana, is a reproductive toxicant in both man and animals. THC acts at both the level of the pituitary-hypothalamic axis and the testis, specifically the Leydig cell; an effect on the Sertoli cell has not been shown. Since THC inhibits cAMP accumulation in several cell types, we have examined the effect of THC on Sertoli cell function using altered cAMP accumulation as a marker of toxicity. THC reduced the FSH-induced accumulation of cAMP at concentrations which were neither cytotoxic nor affected cellular ATP levels. This inhibition was evident after 3 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that THC does not compete with FSH for binding to its receptor. The ability of THC to inhibit cAMP accumulation was not affected by incubation in the presence of phosphodiesterase inhibitors, making it unlikely that it acts via stimulation of phosphodiesterase activity. This THC-induced inhibition of Sertoli cell cAMP is specific for FSH; it does not affect the ability of forskolin, cholera toxin, isoproterenol, or prostaglandin E1 to stimulate Sertoli cell cAMP. Furthermore, inhibition occurs in the presence of pertussis toxin, suggesting that this effect of THC is independent of the inhibitory adenylate cyclase pathway. Inhibition of Sertoli cell cAMP also occurs with other cannabinoids which are present in marihuana, but which are not psychoactive. These data indicate that a part of the testicular toxicity of THC may be due to a specific alteration of the hormonal control of Sertoli cell function via an inhibition of FSH-stimulated cAMP accumulation.
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PMID:Specific inhibition of FSH-stimulated cAMP accumulation by delta 9-tetrahydrocannabinol in cultures of rat Sertoli cells. 255 14

Luteinizing hormone is the major regulator of Leydig cell differentiation and steroidogenic function. A number of hormones produced by the Leydig cell (e.g. estrogen, angiotensin, CRF, vasopressin) and the tubular compartment (inhibin, TGF beta), can influence both acute and long-term actions of LH. Conversely, hormones produced in the Leydig cells modulate tubular function (e.g. androgen, beta-endorphin, oxytocin). The LH stimulatory event can be negatively influenced by the action of angiotensin II through the guanyl nucleotide inhibitory unit of adenylate cyclase. We have recently discovered an action of corticotrophin releasing hormone through specific high-affinity low-capacity receptors in the Leydig cells which involves a pertussis toxin insensitive guanyl nucleotide regulatory unit with interaction between signalling pathways and resulting inhibition of LH induced cAMP generation and consequently of steroidogenesis. In contrast to other tissues the CRF receptor in the Leydig cells did not couple to Gs. CRF action is exerted through direct or indirect action of protein kinase C, at the level of the catalytic subunit of adenylate cyclase. Physiological increases in endogenous LH cause positive regulation of membrane receptors and steroidogenesis, while major elevations in circulating gonadotropin can induce down-regulation of LH receptors and desensitization of steroid responses in the adult cell. Gonadotropin-induced desensitization in adult rat tests include an estrogen mediated steroidogenic lesion of the microsomal enzymes 17 alpha-hydroxylase/17,20-desmolase. For further understanding of the regulation of this key enzyme of the androgen pathway the rat P450(17) alpha cDNA was cloned and sequenced. This cDNA expressed in COS-1 cells 17 alpha-hydroxylase/17,20-desmolase activities. From the deduced amino acid sequence, two transmembrane regions were identified, a signal peptide for insertion in the ER, and a 2nd transmembrane region separated from the first by 122 amino acids. The carboxy terminal non-transmembrane region possesses 4 hydrophobic clefts, of which cleft II would contain the putative steroid binding site for both hydroxylase and lyase activities. The rat cDNA was employed to evaluate the hormonal regulation of mRNA levels in adult and fetal Leydig cells. Low dose hCG treatment caused an early increase in mRNA levels followed by a return to control values at later times, while with higher desensitizing doses the initial increase in mRNA was followed by a marked reduction in mRNA at 24 h and a small recovery at 48 h. Fetal rat Leydig cells treated with E2 showed a 70% decrease in P450 mRNA levels, and testosterone production closely followed the changes in mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:LH action in the Leydig cell: modulation by angiotensin II and corticotropin releasing hormone, and regulation of P450(17) alpha mRNA. 269 45

Rat Leydig cells possess functional high-affinity receptors for angiotensin II (AII). AII inhibits adenylate cyclase activity in Leydig cell membranes and reduces basal and human chorionic gonadotropin (hCG)-stimulated cAMP pools and testosterone production in intact cells. Treatment of cells with an inhibitory dose of forskolin (10(-9) M) and a submaximal dose of AII caused additive inhibition of hCG-stimulated events. The inhibitory action of AII was largely prevented by pertussis toxin prior to the addition of AII alone or in the presence of hCG. This study and our recent report on inhibitory action of low doses of forskolin, 10(-12)-10(-9) M (Khanum, A., and Dufau, M.L. (1986) J. Biol. Chem. 261, 11456-11459) are indicative of a pertussis toxin-sensitive subunit of adenylate cyclase available for acute regulation of Leydig cell function. 8-bromo-cAMP bypasses the inhibitory effect of forskolin as well as AII. We have, therefore, demonstrated functional AII high-affinity receptor and an acute inhibitory effect of AII on hCG action in Leydig cells. Our results have provided evidence for a pertussis toxin-sensitive guanine nucleotide inhibitory protein as mediator of the effect of AII. These findings further emphasized the importance of the cAMP pathway in the Leydig cells, and studies also suggest that tubular and locally produced AII could negatively modulate luteinizing hormone stimulation of Leydig cells.
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PMID:Angiotensin II receptors and inhibitory actions in Leydig cells. 283 94

The role of temperature and testicular descent in postnatal appearance of inhibitory guanine nucleotide-binding regulatory protein (G(i)) function was studied in the rat testis. Dispersed testicular cells of 5-day-old rats were incubated for 24 h at 32 or 37 C, then for another 24 h at the same temperatures in the presence and absence of pertussis toxin (PT; 100 micrograms/liter), and finally for a third 24-h period with cholera toxin (CT; 500 ng/liter) with or without PT. At both temperatures, PT treatment significantly (P < 0.05) increased the CT-stimulated cAMP output, but had no effect on basal cAMP production. When testosterone (T) production, as an indicator of Leydig cell function, was measured in the same incubation, CT-stimulated T production was greater at 32 C, but PT had no effect at either temperature. A similar finding was made when hCG (10 micrograms/liter), instead of CT, was used as the stimulus of T production. Hence, a functional G(i) protein is present in seminiferous tubules of 5-day-old testes cultured for 3 days at 32 and 37 C, but not in Leydig cells. We then examined the effects of longer exposure of 5-day-old testes to the two temperatures. After culture for 7 days with 0.1 microgram/liter ovine LH, the presence of PT at 32 C significantly (P < 0.01) enhanced CT-stimulated T production during the last 24 h of culture, but the PT effect was not observed when the culture was carried out at 37 C. Hence, G(i)-mediated modulation of Leydig cell function appears to require several days of induction at the lower temperature of 32 C. As the postnatal descent also changes the ambient testicular temperature, we next studied whether this event alters the G(i) protein function of Leydig cells. Five-day-old rats were rendered bilaterally cryptorchid or sham operated, and studied after 12 days. Testis weights did not differ between the abdominal and scrotal testes. In contrast, the basal and hCG-stimulated rates of T production were significantly (P < 0.01-0.05) higher in the scrotal testes. When dispersed cells of the scrotal and abdominal testes were incubated for 24 h at 37 C in the presence of CT with or without PT, enhancement of T production by PT was only observed in cells of the scrotal testes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A novel role for testicular descent; temperature-dependent induction of pertussis toxin-sensitive Gi protein function in postnatal rat Leydig cells. 766 86

Corticotropin-releasing factor (CRF), the key neuropeptide in the stress cascade, has major inhibitory actions on testicular function in addition to its known antireproductive effects at the central level (inhibition of sexual behavior and LH secretion). CRF is secreted by the Leydig cells of the testis and acts through high-affinity receptors at the Leydig cell membrane as a potent negative regulator of LH action, inhibiting gonadotropin-induced cAMP generation and androgen production. CRF is also a primary stimulus of beta-endorphin secretion by the Leydig cells, which in turn exerts paracrine inhibition of FSH action in the tubular compartment of the testis through high-affinity receptors in the Sertoli cells. CRF action in the Leydig cells involves a pertussis toxin-insensitive guanyl nucleotide regulatory unit. In contrast to CRF receptors in the brain, pituitary, and other peripheral tissues, those in the Leydig cell are not coupled to Gs. The inhibitory action of CRF in the Leydig cell is exerted through protein kinase C, at the level of the catalytic subunit of adenylate cyclase. The secretion of CRF by the Leydig cell is stimulated by LH, acting via release of serotonin (5HT) and autocrine activation of 5HT2 receptors. Serotonin acts on 5HT2 receptors in the Leydig cell to stimulate CRF secretion via a pertussis toxin insensitive G-protein and presumably through activation of phosphoinositide hydrolysis. The diversity of the biochemical responses to CRF and 5HT2 receptor activation (i.e., inhibition of adenylate cyclase at the cytoplasmic aspect of the cell membrane vs. stimulation of CRF release from secretion granules) may reflect the stimulation of different protein kinase C isoenzymes. The LH-->5HT-->CRF inhibitory loop serves to continuously buffer the stimulation of androgen production by gonadotropin. 5HT, the immediate stimulus of testicular CRF secretion, is released during stress and is locally increased in the testis in pathological conditions associated with impaired testicular function (i.e., orchitis, varicocele). Also, propranolol, the beta-adrenergic antagonist frequently used in the control of blood pressure in patients with hypertension and often associated with impotence, acts via a serotonergic mechanism to stimulate CRF secretion and causes marked inhibition of LH-induced cAMP production and steroidogenesis in cultured Leydig cells. These basic studies of 5HT and CRF are relevant to the pathogenesis of testicular dysfunction and for the development of antagonist therapies to block CRF production and its local antireproductive effects.
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PMID:Corticotropin-releasing factor: an antireproductive hormone of the testis. 838 38

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