Pharmacological characterization of the ATP-dependent low Km guanosine 3′,5′-cyclic monophosphate (cGMP) transporter in human erythrocytes

Sundkvist, Elisabeth; Jaeger, Ragnhild; Sager, Georg

doi:10.1016/s0006-2952(01)00940-6

Cited by 39 publications

(28 citation statements)

References 24 publications

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“…In Drosophila tubules, both cGMP and cAMP transport were both reduced at high concentrations of methotrexate; this reduction became statistically significant at a concentration of 4·mmol·l -1 . Although the ABCG inhibitor mitoxantrone has not been shown to affect cGMP transport in erythrocytes (Sundkvist et al, 2002), treatment of tubules with mitoxantrone did impact on cGMP transport; at 20·mol·l -1 the ratio of cGMP transport by tubules was reduced to 27% of that of untreated control tubules (Table·1).…”

Section: Abcgmentioning

confidence: 95%

A new role for a classical gene: White transports cyclic GMP

Evans

Day

Cabrero

et al. 2008

Journal of Experimental Biology

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SUMMARYGuanosine 3Ј-5Ј cyclic monophosphate (cGMP) and adenosine 3Ј-5Ј cyclic monophosphate (cAMP) are important regulators of cell and tissue function. However, cGMP and cAMP transport have received relatively limited attention, especially in model organisms where such studies can be conducted in vivo. The Drosophila Malpighian (renal) tubule transports cGMP and cAMP and utilises these as signalling molecules. We show here via substrate competition and drug inhibition studies that cAMP transport -but not cGMP transport -requires the presence of di-or tri-carboxylates; and that transport of both cyclic nucleotides occurs via ATP binding cassette sub-family G2 (ABCG2), but not via ABC sub-family C (ABCC), transporters. In Drosophila, the white (w) gene is known for the classic eye colour mutation. However, gene expression data show that of all adult tissues, w is most highly expressed in Malpighian tubules. Furthermore, as White is a member of the ABCG2 transporter class, it is a potential candidate for a tubule cGMP transporter. Assay of cGMP transport in w -(mutant) tubules shows that w is required for cGMP transport but not cAMP transport. Targeted over-expression of w in w -tubule principal cells significantly increases cGMP transport compared with that in w -controls. Conversely, treatment of wild-type tubules with cGMP increases w mRNA expression levels, implying that cGMP is a physiologically relevant substrate for White. Immunocytochemical localisation reveals that White is expressed in intracellular vesicles in tubule principal cells, suggesting that White participates in vesicular transepithelial transport of cGMP.

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Section: Abcgmentioning

confidence: 95%

A new role for a classical gene: White transports cyclic GMP

Evans

Day

Cabrero

et al. 2008

Journal of Experimental Biology

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“…On the other hand, cGMP is rapidly degraded by cGMP-specific PDE5. In addition to degradation by phosphodiesterases, cyclic nucleotide elimination pathways comprise active export into the extracellular space via members of the multidrug resistance protein (MRP) family (also known as ATP-binding cassette transporter family) (41,44). MRPs are localized in the plasma membrane, bind and hydrolyze ATP, and provide the energy to transport their substrates across membrane barriers.…”

mentioning

confidence: 99%

Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle

Al‐Shboul

Mahavadi

Sriwai

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Al-Shboul O, Mahavadi S, Sriwai W, Grider JR, Murthy KS. Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle. Am J Physiol Gastrointest Liver Physiol 305: G314-G324, 2013. First published June 13, 2013; doi:10.1152/ajpgi.00457.2012.-Previous studies have identified differences in the expression of proteins that regulate myosin light chain phosphorylation and contraction in tonic and phasic smooth muscle. cGMP plays a critical role in smooth muscle relaxation and is important for optimal function of phasic and tonic smooth muscle. The intracellular cGMP levels are regulated by its hydrolysis via phosphodiesterase 5 (PDE5) and efflux via novel multidrug resistance protein 5 (MRP5). In the present study we tested the hypothesis that the differences in the phasic and tonic behavior of smooth muscles may be related to differences in mechanisms that terminate cGMP signaling. Expression of PDE5 and MRP5 was significantly (more than 2-fold) higher in fundus compared with antrum. The NO donor S-nitrosoglutathione (GSNO) caused an increase in PDE5 activity and intra-and extracellular cGMP levels in both fundus and antrum. Stimulation of PDE5 activity and increase in extracellular cGMP were significantly higher in fundus, whereas increase in intracellular cGMP was significantly higher in antrum. GSNO-induced increase in extracellular cGMP was blocked in dispersed cells by the cyclic nucleotide export blocker probenecid and in cultured muscle cells by depletion of ATP or suppression of MRP5 by siRNA, providing evidence that cGMP efflux was mediated by ATPdependent export via MRP5. Consistent with the higher expression and activity levels of PDE5 and MRP5, GSNO-induced PKG activity and muscle relaxation were significantly lower in muscle cells from fundus compared with antrum. Thus higher expression of PDE5 and MRP5 in muscle cells from fundus correlates with tonic phenotype of muscle. cyclic nucleotides; MRP5; phasic muscle; tonic muscle GASTROINTESTINAL TRACT smooth muscle possesses distinct regional and functional properties that distinguish it from other types of visceral and vascular smooth muscle. An essential step in smooth muscle contraction is phosphorylation of the 20-kDa regulatory myosin light chain (MLC 20 ) by a Ca 2ϩ /calmodulindependent or -independent myosin light chain (MLC) kinase (MLCK) that transfers the phosphate group from ATP to Ser 19 (16,20,30,43,45,46). Smooth muscle relaxation is initiated by targeting MLC 20 dephosphorylation (43). Most agents cause relaxation by stimulating the production of cAMP (e.g., vasoactive intestinal peptide and its homologue pituitary adenylate cyclase-activating peptide) or cGMP [e.g., nitric oxide (NO)] leading to activation of PKA, PKG, or both (25,26,30,43). cAMP-activated PKA and cGMP-activated PKG are the main enzymes that induce relaxation in smooth muscle. They target different components of the contractile signaling pathways that attenuate MLCK activity and/or augment ...

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“…Studies with human erythrocytes have shown that the organic anionic pump which transports cGMP to extracellular area is dependent on a) ATP, b) its hydrolysis, and on c) the stimulation of ATPase activity by the cGMP itself (Sundkvist et al, 2002). PDE inhibitors block this transport.…”

Section: Vas Deferensmentioning

confidence: 99%

“…Sildenafil inhibiting PDE5 increases cGMP in the vas deferens muscular fibers and additionally blocks the activity of this organic anion pump. The overall result is an increase in the intracellular cGMP by a) prevention of the destruction of cGMP and b) inhibition of cGMP extracellular export (Sundkvist et al, 2002).…”

Section: Vas Deferensmentioning

confidence: 99%