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)

In killifish renal proximal tubules, endothelin-1 (ET-1), acting through a basolateral ET(B) receptor, nitric oxide synthase (NOS), and PKC, decreases cell-to-lumen organic anion transport mediated by the multidrug resistance protein isoform 2 (Mrp2). In the present study, we examined the roles of guanylyl cyclase and cGMP in ET signaling to Mrp2. Using confocal microscopy and quantitative image analysis to measure Mrp2-mediated transport of the fluorescent drug fluorescein methotrexate (FL-MTX), we found that oxadiazole quinoxalin (ODQ), an inhibitor of NO-sensitive guanylyl cyclase, blocked ET-1 signaling. ODQ was also effective when signaling was initiated by nephrotoxicants (gentamicin, amikacin, diatrizoate, HgCl(2), and CdCl(2)), which appear to stimulate ET release from the tubules themselves. ODQ blocked the effects of the NO donor sodium nitroprusside but not of the phorbol ester that activates PKC. Exposing tubules to 8-bromo-cGMP (8-BrcGMP), a cell-permeable cGMP analog, decreased luminal FL-MTX accumulation. This effect was abolished by bisindoylmaleimide (BIM), a PKC inhibitor, but not by N(G)-methyl-l-arginine, a NOS inhibitor. Together, these data indicate that ET regulation of Mrp2 involves activation of guanylyl cyclase and generation of cGMP. Signaling by cGMP follows NO release and precedes PKC activation.
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PMID:Involvement of guanylyl cyclase and cGMP in the regulation of Mrp2-mediated transport in the proximal tubule. 1497 2

We previously showed that the function of renal multidrug resistance protein (Mrp) 2 (Abcc2) is reduced by endothelin (ET)-1 signaling through an ET(B) receptor, nitric-oxide synthase (NOS), cGMP, and protein kinase C and that this pathway was activated by several nephrotoxicants (Masereeuw et al., 2000; Terlouw et al., 2001; Notenboom et al., 2002, 2004). Here, we determined the long-term effects on Mrp2-mediated transport (luminal fluorescein methotrexate accumulation) of short-term (30 min) exposure to ET-1 and the aminoglycoside antibiotic, gentamicin. Our data show that over the 3 h following exposure, proximal tubules recovered fully from the initial decrease in Mrp2-mediated transport and that transport activity was not changed 9 h later. However, 24 h after exposure, luminal accumulation of an Mrp2 substrate had increased by 50%. Increased transport at 24 h was accompanied by an increased transporter protein content of the luminal plasma membrane as measured by immunostaining. Blocking ET-1 signaling at the ET(B) receptor or downstream at NOS or guanylyl cyclase abolished both stimulation of transport and increased transporter expression. Thus, regardless of whether signaling was initiated by a short exposure to ET-1 or to a nephrotoxicant, the time course of Mrp2 response to ET(B) signaling was the same and was multiphasic. Finally, when tubules were exposed to gentamicin for 30 min and removed to gentamicin-free medium for 24 h, they were less sensitive to acute gentamicin toxicity than paired controls not initially exposed to the drug. Thus, short-term exposure to ET-1 or gentamicin resulted in long-term protection against a second insult.
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PMID:Short-term exposure of renal proximal tubules to gentamicin increases long-term multidrug resistance protein 2 (Abcc2) transport function and reduces nephrotoxicant sensitivity. 1608 57

The multidrug resistance protein 4 (MRP4) is a member of the ABCC subfamily of the adenosine triphosphate-binding cassette transporters that remove cyclic nucleotides from platelets and uptake ADP into dense granule in platelets. However, whether MRP4 directly involves platelet activation remains unclear. Thus, the aim of our study was to determine the detailed mechanisms underlying the regulation of MRP4 in platelet activation. Our results revealed that the MRP4 inhibitor MK571 inhibited collagen-induced platelet aggregation which was partially reversed by the PKA inhibitor H89, but not by the adenylyl cyclase (AC) inhibitor SQ22536 and the guanylyl cyclase (GC) inhibitor ODQ, suggesting that MK571 can prevent collagen-induced aggregation via a route independent of cyclic nucleotide production. In the present study, we found that MK571 inhibited collagen-induced ATP release and calcium mobilization. The phosphorylation of protein kinase C, JNK, and Akt was also inhibited by MK571, and electron spin resonance experiment showed that MK571 significantly reduced hydroxyl radical formation. Moreover, MK571 delayed platelet plug formation in vitro by a PFA-100 device, and delayed thrombus formation in mesenteric venules of mice irradiated by fluorescein sodium. However, previous studies have reported that MK571 also blocks MRP1 and leukotriene D4 (LTD4) receptor. Therefore, whether MK571 inhibits platelet activation through MRP1 or LTD4 receptor needs to be considered and further defined. In conclusion, in addition to blocking the transport of cyclic nucleotides, MRP4 inhibition may prevent thrombus formation in vitro and in vivo. Our findings also support the idea that MRP4 may represent a potential target for the development of novel therapeutic interventions for the treatment of thromboembolic disorders.
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PMID:Multidrug resistance protein 4 (MRP4/ABCC4) regulates thrombus formation in vitro and in vivo. 2483 86