Export of guanosine 3′,5′-cyclic monophosphate (cGMP) from human erythrocytes characterized by inside-out membrane vesicles

Sager, Georg; Ørbo, Anne; Pettersen, R H; Kjørstad, Kjell E.

doi:10.3109/00365519609090579

Cited by 35 publications

(37 citation statements)

References 21 publications

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“…The knowledge about the structure and function of the protein families involved in cGMP synthesis and degradation has grown vastly the last years, whereas little was known so far about the molecular identity of the proteins that mediate the cellular export. Studies in membrane vesicles from human erythrocytes suggested that cGMP is transported by an organic anion transport ATPase (12)(13)(14). The reported characteristics of this transport system in erythrocytes, including the K m value of 2.4 M for cGMP (13) and the lack of affinity for the MRP1 substrate leukotriene C 4 (14), are similar to our findings on MRP5-mediated cGMP transport (see Fig.…”

Section: Discussionsupporting

confidence: 90%

“…Both cAMP, as well as cGMP, secretion has been shown to be unidirectional and energy-dependent (4 -8, 10). Furthermore, a primary active transport of cGMP has been demonstrated directly in inside-out membrane vesicles from human erythrocytes (12)(13)(14). The transport of both cyclic nucleotides has been shown to be inhibited by probenecid, suggesting that this export is mediated by a transporter for amphiphilic anions (10,13,15).…”

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confidence: 97%

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The Multidrug Resistance Protein 5 Functions as an ATP-dependent Export Pump for Cyclic Nucleotides

Jedlitschky¹,

Burchell²,

Keppler³

2000

Journal of Biological Chemistry

404

335

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Cellular export of cyclic nucleotides has been observed in various tissues and may represent an elimination pathway for these signaling molecules, in addition to degradation by phosphodiesterases. In the present study we provide evidence that this export is mediated by the multidrug resistance protein isoform MRP5 (gene symbol ABCC5). The transport function of MRP5 was studied in V79 hamster lung fibroblasts transfected with a human MRP5 cDNA. An MRP5-specific antibody detected an overexpression of the glycoprotein of 185 ؎ 15 kDa in membranes from MRP5-transfected cells and a low basal expression of hamster Mrp5 in control membranes. ATP-dependent transport of 3,5-cyclic GMP at a substrate concentration of 1 M was 4-fold higher in membrane vesicles from MRP5-transfected cells than in control membranes. This transport was saturable with a K m value of 2.1 M. MRP5-mediated transport was also detected for 3,5-cyclic AMP at a lower affinity, with a K m value of 379 M. A potent inhibition of MRP5-mediated transport was observed by several compounds, known as phosphodiesterase modulators, including trequinsin, with a K i of 240 nM, and sildenafil, with a K i value of 267 nM. Thus, cyclic nucleotides are physiological substrates for MRP5; moreover, MRP5 may represent a novel pharmacological target for the enhancement of tissue levels of cGMP.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 97%

The Multidrug Resistance Protein 5 Functions as an ATP-dependent Export Pump for Cyclic Nucleotides

Jedlitschky¹,

Burchell²,

Keppler³

2000

Journal of Biological Chemistry

404

335

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“…Erythrocyte membranes express at least two transporters for glutathione conjugates [2,4,45], one with a high affinity for DNP-SG (K d ~2 μM) and identifiable as MRP1 and another with a low affinity (K d > ~60 μM) [4]. There are also cGMP transporters, one with a low affinity (K d 50 -80 μM) [4] and another with a high affinity (K d ~ 1 μM) [46]. This latter probably contributes less, perhaps much less, than 20% of the transport even at the lowest concentrations [4].…”

Section: Discussionmentioning

confidence: 99%

Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes

Klokouzas

Hladky

et al. 2005

Biochemical Pharmacology

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Human erythrocyte membranes express the multidrug resistance-associated proteins, MRP1, MRP4 and MRP5, that collectively can efflux oxidised glutathione, glutathione conjugates and cyclic nucleotides. It is already known that the quinoline derivative, MK-571, is a potent inhibitor of MRPmediated transport. We here examine whether the quinoline-based antimalarial drugs, amodiaquine, chloroquine, mefloquine, primaquine, quinidine and quinine, also interact with erythrocyte MRPs with consequences for their access to the intracellular parasites or for efflux of oxidised glutathione from infected cells. Using inside-out vesicles prepared from human erythrocytes we have shown that mefloquine and MK-571 inhibit transport of 3 μM [ 3 H]DNP-SG known to be mediated by MRP1 (IC 50 127 μM and 1.1 μM respectively) and of 3.3 μM [ 3 H]cGMP thought but not proven to be mediated primarily by MRP4 (IC 50 21 μM and 0.41 μM). They also inhibited transport in membrane vesicles prepared from tumour cells expressing MRP1 or MRP4 and blocked calcein efflux from MRP1 overexpressing cells and BCECF efflux from MRP4 overexpressing cells. Both stimulated ATPase activity in membranes prepared from MRP1 and MRP4 overexpressing cells and inhibited activity stimulated by quercetin or PGE 1 respectively. Neither inhibited [α-32 P]8-azidoATP binding confirming that the interactions are not at the ATP binding site. These results demonstrate that mefloquine and MK-571 both inhibit transport of other substrates and stimulate ATPase activity and thus may themselves be substrates for transport. But at concentrations achieved clinically mefloquine is unlikely to affect the MRP1-mediated transport of GSSG across the erythrocyte membrane.

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“…Although an initial report suggested that MRP4 is a high-affinity cGMP transporter [24], this was not confirmed by later work (see Table 1). An accumulating body of indirect evidence [103] suggests that MRP4 is the main transporter responsible for the efflux of messenger cGMP from erythrocytes [24,48,85,89,93,104]. However, all experiments were conducted in vitro with inside-out membrane vesicles prepared from either cultured cell lines or erythrocytes.…”

Section: Cyclic Nucleotide Transport By Mrp4mentioning

confidence: 99%

“…cGMP efflux from intact erythrocytes has not yet been demonstrated and there is no evidence that mature erythrocytes can actually make cGMP. The physiological relevance of cGMP efflux by MRP4 from erythrocytes is, therefore, questionable, especially as MRP4 transports cGMP with low affinity [48,85,101]. In view of the observed high rate of cGMP transport by erythrocyte vesicles, MRP4 might limit the ability of erythrocytes to accumulate base/nucleoside analogs.…”

Section: Cyclic Nucleotide Transport By Mrp4mentioning

confidence: 99%

Multidrug resistance-associated proteins 3, 4, and 5

Borst

Wolf

Wetering

2006

Pflugers Arch - Eur J Physiol

273

260

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We summarize in this paper the recently published results on multidrug resistance-associated proteins 3, 4, and 5 (MRPs 3-5). MRP3 can transport organic compounds conjugated to glutathione, sulfate, or glucuronate, such as estradiol-17beta-glucuronide, bilirubin-glucuronides, and etoposide-glucuronide, and also bile salts and methotrexate. Studies in knockout mice have shown that Mrp3 contributes to the transport of morphine-3-glucuronide and acetaminophen-glucuronide from the liver into blood. There is no evidence for a major role of MRP3 in bile salt metabolism, at least in mice. The function of MRP3 in other tissues, notably the gut and the adrenal cortex, remains to be defined. MRP4 and MRP5 have attracted attention by their ability to transport cyclic nucleotides and many nucleotide analogs. The initial reports that MRP4 and 5 can transport cGMP with microM affinity have not been confirmed in recent work and the physiological importance of cyclic nucleotide transport by MRP4 and 5 remains to be determined. Transfected cells containing high concentrations of MRP4 and 5 are moderately resistant to base, nucleoside, and nucleotide analogs. The affinity of both transporters for nucleotide analogs is low (K (m) around 1 mM) and there is no evidence that the transport of these compounds results in resistance in vivo. The physiological function of MRP4 and 5 remains to be found.

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Export of guanosine 3′,5′-cyclic monophosphate (cGMP) from human erythrocytes characterized by inside-out membrane vesicles

Cited by 35 publications

References 21 publications

The Multidrug Resistance Protein 5 Functions as an ATP-dependent Export Pump for Cyclic Nucleotides

The Multidrug Resistance Protein 5 Functions as an ATP-dependent Export Pump for Cyclic Nucleotides

Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes

Multidrug resistance-associated proteins 3, 4, and 5

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