Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both testosterone and cyclic GMP stimulate DNA synthesis. Because cyclic GMP and testosterone seem to have similar actions, the objective of this investigation was to determine if testosterone and its precursors might have part of their mechanism of action through stimulation of guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2], the enzyme that catalyzes the formation of cyclic GMP from GTP. The precursors--namely, progesterone, pregnenolone, 17 alpha-progesterone, 17 alpha-hydroxypregnenolone, androstenedione, and dehydroepiandrosterone--caused a 2- to 3 1/2-fold enhancement of guanylate cyclase activity in rat liver, kidney, skeletal muscle, and ventral prostate at a concentration of 1 microM. These precursors are generated from cholesterol, which had no effect itself on guanylate cyclase activity. Testosterone, 19-nortestosterone, 17-methyltestosterone, and 5 alpha-dihydrotestosterone enhanced guanylate cyclase activity 2- to 5-fold in the same tissues at 1 microM. Etiocholanolone, androsterone, and epiandrosterone, metabolites of testosterone metabolism, enhanced guanylate cyclase activity 1 1/2- to 2-fold at this same concentration. Dose-response relationships revealed that testosterone and its precursors and metabolites had their maximal effect at 1 microM but still had some effect at 0.001 microM. The data in this investigation suggest that the guanylate cyclase-cyclic GMP system plays a role in the mechanism of action of testosterone and its precursors.
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PMID:Testosterone and its precursors and metabolites enhance guanylate cyclase activity. 4 Feb 26

The effects of different atrial natriuretic peptides on cyclic GMP formation and steroidogenesis have been studied in Percoll-purified mouse Leydig cells. Rat atrial peptides rANP (rat atrial natriuretic peptide), rAP-I (rat atriopeptin I) and rAP-II (rat atriopeptin II), in the presence of a phosphodiesterase inhibitor, stimulated cyclic GMP formation in a concentration-dependent manner. In the presence of saturating concentrations of the peptides, a 400-600 fold stimulation of cyclic GMP accumulation was observed. Among the peptides, rAP-II appeared to be the most potent. ED50 values (concentration causing half-maximal effect) for rAP-II, rANP and rAP-I were 1 X 10(-9) M, 2 X 10(-9) M and 2 X 10(-8) M respectively. A parallel stimulation of cyclic GMP formation and testosterone production by the cells was observed after incubation of the cells with various concentrations of rAP-II. In the presence of a saturating concentration of rAP-II (2 X 10(-8) M), maximum stimulation of intracellular cyclic GMP content was obtained within 5 min of incubation. Testosterone production by mouse Leydig cells could be stimulated by 8-bromo cyclic GMP in a concentration-related manner. At a 10 mM concentration of the cyclic nucleotide, steroidogenesis was stimulated to a similar extent as that obtained with a saturating concentration of human chorionic gonadotrophin (5 ng/ml). On the basis of these results we conclude that cyclic GMP acts as a second messenger in atrial-peptide-stimulated steroidogenesis in mouse Leydig cells. The steroidogenic effect of atrial peptides appears to be species-specific, since none of these peptides stimulated testosterone production by purified Leydig cells of rats, though in these cells a 40-60-fold stimulation of cyclic GMP formation in response to each of the three peptides was observed. However, 8-bromo cyclic GMP could stimulate testosterone production in rat Leydig cells. Therefore we conclude that the lack of steroidogenic response in rat Leydig cells to atrial-natriuretic-factor-stimulation results from an insufficient formation of cyclic GMP in these cells. This species difference would appear to result from a lower guanylate cyclase activity in rat Leydig cells.
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PMID:Steroidogenic effect of atrial natriuretic factor in isolated mouse Leydig cells is mediated by cyclic GMP. 302 72

In this report, we describe the effects of a recently described atrial natriuretic peptide (ANP) antagonist, HS-142-1, on the action of ANP on Percoll-purified mouse Leydig cells. Incubation of the Leydig cells with 10(-8) M ANP for 3 h resulted in a 16-fold stimulation of testosterone production over basal. Addition of HS-142-1 in a concentration range of 0.1 to 5 micrograms/ml resulted in a dose-dependent inhibition of ANP-induced testosterone production, a nearly complete inhibition being achieved with 5 micrograms/ml antagonist. Testosterone production by unstimulated cells or in cells stimulated with hCG was not affected by the antagonist. HS-142-1 was also able to inhibit the ANP-stimulated cyclic guanosine monophosphate (GMP) formation in the cells, in a dose-dependent manner. However, cyclic AMP level in cells stimulated with either forskolin or hCG remained unaffected by HS-142-1 even when added at a concentration of 5 micrograms/ml. Results obtained from 125I-ANP binding experiments showed that HS-142-1 is able to competitively inhibit the binding of the radioligand to its receptors on the Leydig cells. Thus evidence obtained in this study permit us to conclude that HS-142-1 is a potent and specific antagonist of ANP, has no toxic effect on the cells and is able to inhibit competitively the binding of ANP to its guanylate cyclase coupled receptors. Availability of such antagonists are likely to facilitate research on the physiology of ANP.
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PMID:HS-142-1 inhibits testosterone production and guanosine-3':5'-cyclic monophosphate accumulation stimulated by atrial natriuretic peptide in isolated mouse Leydig cells. 769 Jul 21

We have investigated the mechanism by which different natriuretic peptides stimulate steroidogenesis in purified mouse Leydig cells. In addition to atrial natriuretic factor (ANF), we show that brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) also stimulate testosterone production in these cells. Testosterone production was increased dramatically to 14-fold with ANF (EC50 = 0.3 nM) and 15-fold with BNP (EC50 = 0.2 nM); however, the CNP-stimulated level of testosterone production was only 2.5-fold compared with controls. ANF and BNP enhanced the stimulatory effect of LH on testosterone production. The C-ANF(4-23) (a truncated form of ANF) had no effect on testosterone production in these cells. ANF, BNP, and CNP stimulated the production of intermediate precursors of testosterone biosynthesis, which included progesterone, 17 alpha-hydroxy progesterone, androstenedione, pregnenolone, 17 alpha-hydroxy pregnenolone, and dehydroepiandrosterone sulfate. The conversion of pregnenolone and progesterone to testosterone was also significantly enhanced after treatment of Leydig cells with these peptides. All three natriuretic peptides (ANF, BNP, and CNP) stimulated the activity of particulate guanylate cyclase by 8.4-, 8.5-, and 4.8-fold and the accumulation of intracellular cGMP by 52-, 58-, and 19-fold, respectively. The cGMP inhibitor LY83583 attenuated both the generation of cGMP as well as testosterone in response to these natriuretic peptides, suggesting the involvement of cGMP as a second messenger. Leydig cells were found to contain high affinity and low capacity binding sites for ANF [dissociation constant (Kd), 2.0 x 10(-10) M; maximum binding capacity (Bmax). 20 fmol/1 x 10(5) cells], BNP (Kd, 2.2 x 10(-10) M; Bmax, 19 fmol/1 x 10(5) cells), and CNP (Kd, 3.1 x 10(-10) M; Bmax, 8.6 fmol/1 x 10(5) cells). The results presented here document that a family of different natriuretic peptides stimulates Leydig cell steroidogenesis in receptor-mediated fashion, beginning at the cholesterol side-chain cleavage enzyme. The data also show that these peptide hormones induce testosterone production in mouse Leydig cells by involving both delta 4- and delta 5-pathways of steroidogenesis.
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PMID:Receptor-mediated stimulatory effect of atrial natriuretic factor, brain natriuretic peptide, and C-type natriuretic peptide on testosterone production in purified mouse Leydig cells: activation of cholesterol side-chain cleavage enzyme. 840 64

The cyclic nucleotides involvement in the vasorelaxation induced by testosterone in human umbilical artery was investigated. The effect of this hormone on denuded human umbilical arteries contracted by serotonin (5-HT), histamine or KCl was analysed. Testosterone effect on potassium current (IK) was also studied in human umbilical artery vascular smooth muscle cells (HUASMC). In general, the relaxant effects of testosterone, sodium nitroprusside (SNP) and atrial natriuretic peptide (ANP) are similar. The testosterone relaxant effect is not different to the induced by the conjoint application of ANP and testosterone. However, the effects of SNP and testosterone seem additive. The inhibition of protein kinase A (PKA) did not modify the testosterone relaxant effect, but protein kinase G (PKG) inhibition significantly reduced the testosterone effect independently of the contractile stimuli. In HUASMC, the IK is mainly constituted by potassium exit through voltage sensitive (KV) and large-conductance Ca2+ activated (BKCa) potassium channels. Testosterone significantly activates the basal IK. SNP does not induce a significant modification in basal or testosterone stimulated IK. In contrast, ANP stimulates the basal IK, but does not increase the testosterone stimulation on IK. The IK increases induced by testosterone or by ANP are not significantly affected by the PKA inhibition, but are completely inhibited by the PKG inhibition. Our results show that testosterone and ANP stimulate the activity of BKCa and KV channels due to PKG activation and suggest that this hormone relaxes by activating particulate guanylate cyclase which increases the cGMP intracellular level.
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PMID:PKG is involved in testosterone-induced vasorelaxation of human umbilical artery. 2044 26