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

With a recently developed method we detected rapid and sequential reorganization of vitamin D receptors (VDR), including their temporary association with fibers, and we showed that calcitriol induces cGMP accumulation around reorganizing VDRs. In this report we first identified the VDR-associated fibers as microtubules: they show immunoreactivity with tubulin antisera and were sensitive to tubulin-disruptive agents. Tubulin-disruptive agents also prevented calcitriol-induced alignment and intranuclear accumulation of VDR and cGMP, but did not prevent the initial cGMP accumulation in the cytoplasm. Then we studied the effect of molybdate on VDR reorganization and on cGMP accumulation. Sodium molybdate inhibits steroid receptor transformation into a DNA binding form through interaction with the steroid binding region of the receptor. The mechanism of molybdate effect on steroid receptors is not well understood and the interaction of molybdate with guanylate cyclase has not been investigated. We found in cells pretreated with molybdate that the addition of calcitriol resulted in a prolonged and accentuated association of VDR and cGMP with the microtubules. Furthermore, both immunocytology and radioimmunoassay demonstrated that molybdate is a highly potent inducer of guanylate cyclase. Neither calcitriol nor molybdate effect on guanylate cyclase were prevented by methylene blue pretreatment, suggesting that they activate particulate guanylate cyclase. Pretreatment of cells with dibutyryl-cGMP mimicked molybdate effect on VDR reorganization. The effect of molybdate on cGMP may participate in molybdate stabilization of steroid receptors. We suggest that rapid cGMP accumulation after steroid exposure plays a role in facilitation of intracellular transport of the steroid receptor through interaction with microtubules.
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PMID:Molybdate increases intracellular 3',5'-guanosine cyclic monophosphate and stabilizes vitamin D receptor association with tubulin-containing filaments. 128 Feb 59

The objective of this investigation was to determine whether physiological levels of vitamin D and its metabolites have part of their mechanisms of action through stimulation of guanylate cyclase (EC 4.6.1.2). These sterols enhanced both soluble and particulate guanylate cyclase activities as well as cGMP levels two- to threefold in human and rat tissues. At a concentration of 1 nM, 1,25(OH)2D3 greater than 25(OH)D3 greater than vitamin D3 greater than 24,25(OH)2D3 = 25,26(OH)2D3 = vitamin D2. Dose-response curves revealed that maximal stimulation of guanylate cyclase by these sterols was at 1 nM and that there was no augmented guanylate cyclase activity at 0.01 nM. The precursors of vitamin D, cholesterol and 7-dehydrocholesterol, had no effect on guanylate cyclase activity. The activation of guanylate cyclase activity by the vitamin D sterols required the presence of manganese ion. Calcium was not as efficient as manganese in optimizing basal or hormone-stimulated guanylate cyclase activity. Vitamin D and its metabolites failed to stimulate adenylate cyclase (EC 4.6.1.1) activity. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of vitamin D at the cellular level.
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PMID:Cation-dependent vitamin D activation of human renal cortical guanylate cyclase. 614 31

The present studies were conducted to determine whether [3H]quinuclidinyl benzilate binding in rat colonic membranes and/or carbachol-mediated stimulation of particulate guanylate cyclase were altered by changes in vitamin D status. EC50 values for the stimulation of colonic guanylate cyclase by carbachol were found to be significantly greater in vitamin D-deficient rats compared to their D-sufficient counterparts. Concomitantly, the density of receptors (Bmax) were significantly lower, and dissociation constants (Kd) were significantly higher in D-deficient colonic membranes. In vitamin D-repleted animals, moreover, all of these aforementioned alterations were at least partially corrected.
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PMID:Vitamin D status modulates rat colonic M3 muscarinic receptor characteristics and coupling to guanylate cyclase. 791 5

Bone remodeling reflects an equilibrium between bone resorption and formation. The local expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in bone determines the entry of monoblastic precursors into the osteoclast lineage and subsequent bone resorption. Nitric oxide (NO) inhibits osteoclastic bone resorption in vitro and regulates bone remodeling in vivo. An interaction of NO with RANKL and OPG has not been studied. Here, we show that treatment of ST-2 murine stromal cells with the NO donor sodium nitroprusside (100 microm) for 24 h inhibited 1,25 dihydroxyvitamin D(3)-induced RANKL mRNA to less than 33 +/- 7% of control level, whereas OPG mRNA increased to 204 +/- 19% of control. NOR-4 replicated these NO effects. The effects of NO were dose dependent and associated with changes in protein levels: RANKL protein decreased and OPG protein increased after treatment with NO. PTH-induced RANKL expression in primary stromal cells was inhibited by sodium nitroprusside, indicating that the NO effect did not require vitamin D. NO donor did not change the stability of RANKL or OPG mRNAs, suggesting that NO affected transcription. Finally, cGMP, which can function as a second messenger for NO, did not reproduce the NO effect, nor did inhibition of endogenous guanylate cyclase prevent the NO effect on these osteoactive genes. The effect of NO to decrease the RANKL/OPG equilibrium should lead to decreased recruitment of osteoclasts and positive bone formation. Thus, drugs and conditions that cause local increase in NO formation in bone may have positive effects on bone remodeling.
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PMID:Nitric oxide regulates receptor activator of nuclear factor-kappaB ligand and osteoprotegerin expression in bone marrow stromal cells. 1456 99

There is considerable need for safe agents that can reduce risk for diabetes in at-risk subjects. Although certain drugs--including metformin, acarbose, and orlistat--have shown diabetes-preventive activity in large randomized studies, nutraceuticals have potential in this regard as well. Natural agents which slow carbohydrate absorption may mimic the protective effect of acarbose; these include: soluble fiber--most notably glucomannan; chlorogenic acid--likely responsible for reduction in diabetes risk associated with heavy coffee intake; and legume-derived alpha-amylase inhibitors. There does not appear to be a natural lipase inhibitor functionally equivalent to orlistat, although there are poorly documented claims for Cassia nomame extracts. Metformin's efficacy reflects activation of AMP-activated kinase; there is preliminary evidence that certain compounds in barley malt have similar activity, without the side effects associated with metformin. In supraphysiological concentrations, biotin directly activates soluble guanylate cyclase; this implies that, at some sufficient intake, biotin should exert effects on beta cells, the liver, and skeletal muscle that favor good glucose tolerance and maintenance of effective beta cell function. Good magnesium status is associated with reduced diabetes risk and superior insulin sensitivity in recent epidemiology; ample intakes of chromium picolinate appear to promote insulin sensitivity in many individuals and improve glycemic control in some diabetics; calcium/vitamin D may help preserve insulin sensitivity by preventing secondary hyperparathyroidism. Although conjugated linoleic acid--like thiazolidinediones, a PPAR-gamma agonist--has not aided insulin sensitivity in clinical trials, the natural rexinoid phytanic acid exerts thiazolidinedione-like effect in animals and cell cultures, and merits clinical examination. Other natural agents with the potential to treat and possibly prevent diabetes include extracts of bitter melon and of cinnamon. Nutraceuticals featuring meaningful doses of combinations of these agents would likely have substantial diabetes-preventive efficacy, and presumably could be marketed legally as aids to good glucose tolerance and insulin sensitivity.
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PMID:Nutraceutical resources for diabetes prevention--an update. 1553 33