Cellular Efflux of cAMP and cGMP - A Question about Selectivity

Sager, Georg; Ravna, Aina Westrheim

doi:10.2174/138955709788681654

Cited by 38 publications

(26 citation statements)

References 51 publications

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“…Under physiological conditions, cytosolic cGMP may be secreted through nucleotide transporters such as CFTR and multidrug resistance proteins (60,61). In human plasma, the cGMP level is 6 nM (62).…”

Section: Discussionmentioning

confidence: 99%

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels

Han

Nie²,

et al. 2011

Am J Respir Cell Mol Biol

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Salt absorption via alveolar epithelial Na 1 channels (ENaC) is a critical step for maintaining an airspace free of flooding. Previously, we found that 8-(4-chlorophenylthio)-guanosine-39,59-cyclic monophosphate-Na (CPT-cGMP) activated native and heterologous ENaC. To investigate the potential pharmacological relevance, we applied this compound intratracheally to human lungs and found that ex vivo alveolar fluid clearance was increased significantly. Furthermore, this compound eliminated self-inhibition in human lung H441 cells and in oocytes expressing human abg but not dbg channels. To further elucidate this novel mechanism, we constructed mutants abolishing (b DV348 and g H233R ) or augmenting (a Y458A and g M432G ) self-inhibition. The mutants eliminating self-inhibition lost their responses to CPT-cGMP, whereas those enhancing self-inhibition facilitated the stimulatory effects of this compound. CPT-cGMP was unable to activate a high P o mutant (b S520C ) and plasmin proteolytically cleaved channels. Our data suggest that elimination of self-inhibition of abg ENaC may be a novel mechanism for CPT-cGMP to stimulate salt reabsorption in human lungs.Keywords: lung fluid reabsorption; amiloride-sensitive sodium channel; CPT-cGMP; ENaC self-inhibition Epithelial Na1 channels (ENaC) in polarized absorptive tight epithelium are responsible for the transapical salt influx. Together with basolaterally located Na 1 /K 1 -ATPase, the vectorial solute/fluid transport pathway is crucial for maintaining luminal and body fluid volume (1-3). Five subunits have been cloned: a, b, g, d, and e ENaC. Luminal impermeable reagents and hormones have been confirmed to regulate salt reabsorption in lung, kidney, and colon.ENaC has long been proposed to function as a ligand-gated channel on the basis of observations of other ENaC/DEG family members (1, 4). Acid-sensing Na 1 channels, a branch of the ENaC/DEG super gene family, are gated by external protons. Another branch of channels, termed FaNaC, are manipulated by FMRFamide and related tetrapeptides (5). With respect to ENaC channels, a number of luminal reagents, including parachloromercuribenzoate; benzimidazoly-2-guanidinium; bumetanide; and H 1 , Zn 21 , and Ni 21 ions, have been reported to alter external Na 1 self-inhibition, a temperature-sensitive intrinsic phenomenon of ENaC (1, 4, 6-10). Recently, a small molecule (S6939), cpt-cAMP, halothane, glibenclamide, and extracellular chloride ions (Cl 2 ) have been shown to act as ligands to regulate heterologous ENaC (11-16). Among these, halothane and Cl 2 ions may activate ENaC by eliminating Na 1 self-inhibition (17, 18). We recently found that 8-(4-chlorophenylthio)-guanosine-39,59-cyclic monophosphate-Na (CPT-cGMP) stimulated human abg ENaC in oocytes in a PKG-independent and domain-specific manner (19). The underlying mechanisms are unknown.Several ectodomains have been reported to modify self-inhibition by unknown mechanisms. Given that self-inhibition is governed by the extracellular Na 1 concentrations, the extracellu...

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Section: Discussionmentioning

confidence: 99%

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels

Han

Nie²,

et al. 2011

Am J Respir Cell Mol Biol

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“…Because mammalian ABCC5 transports cyclic nucleotides (Jedlitschky et al, 2000;Sager and Ravna, 2009;Wielinga et al, 2003), and there is evidence for cAMP signaling in C5a-expressing pigment cells (i.e. expression of Sp-CAPK/PKA; Rast et al, 2002), we tested whether there is a link between cyclic nucleotide signaling and C5a.…”

Section: C5a-mediated Prolapse Is Rescued By Campmentioning

confidence: 99%

“…A number of studies have shown that mammalian ABCC5 transports cyclic nucleotides (Boadu and Sager, 2004;Jedlitschky et al, 2000;Meyer Zu Schwabedissen et al, 2005;Sager and Ravna, 2009;Sager et al, 2012;Wielinga et al, 2003;Wijnholds et al, 2000). cGMP is reported to be a higher-affinity substrate than cAMP, but the exact affinity of cGMP remains unclear Pratt et al, 2005;Reid et al, 2003;Wielinga et al, 2003).…”

Section: Substrates Of C5amentioning

confidence: 99%

“…Among these ABC transporters, ABCC5 (also known as MRP5, MOAT-C, pABC11, sMRP) is unique in that, although being related to proteins involved in protective efflux and drug resistance (Belinsky et al, 1998;Chen and Tiwari, 2011;Kool et al, 1997;McAleer et al, 1999), it has not been demonstrated to be toxicologically important (Chen and Tiwari, 2011;Leslie et al, 2001). That ABCC5 effluxes cGMP and cAMP has long been known (Jedlitschky et al, 2000;Sager and Ravna, 2009;Wielinga et al, 2003); however, more recently, heme (Korolnek et al, 2014) and N-lactoyl-amino acids (Jansen et al, 2015) were reported to be possible substrates. Hyaluronan may also be transported by ABCC5 (Schulz et al, 2007), although it is more likely that it is translocated by hyaluronan synthase itself (Medina et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

et al. 2015

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ATP-binding cassette (ABC) transporters are evolutionarily conserved proteins that pump diverse substrates across membranes. Many are known to efflux signaling molecules and are extensively expressed during development. However, the role of transporters in moving extracellular signals that regulate embryogenesis is largely unexplored. Here, we show that a mesodermal ABCC (MRP) transporter is necessary for endodermal gut morphogenesis in sea urchin embryos. This transporter, Sp-ABCC5a (C5a), is expressed in pigment cells and their precursors, which are a subset of the non-skeletogenic mesoderm (NSM) cells. C5a expression depends on Delta/Notch signaling from skeletogenic mesoderm and is downstream of Gcm in the aboral NSM gene regulatory network. Long-term imaging of development reveals that C5a knockdown embryos gastrulate, but ∼90% develop a prolapse of the hindgut by the late prism stage (∼8 h after C5a protein expression normally peaks). Since C5a orthologs efflux cyclic nucleotides, and cAMP-dependent protein kinase (Sp-CAPK/PKA) is expressed in pigment cells, we examined whether C5a could be involved in gastrulation through cAMP transport. Consistent with this hypothesis, membrane-permeable pCPT-cAMP rescues the prolapse phenotype in C5a knockdown embryos, and causes archenteron hyper-invagination in control embryos. In addition, the cAMP-producing enzyme soluble adenylyl cyclase (sAC) is expressed in pigment cells, and its inhibition impairs gastrulation. Together, our data support a model in which C5a transports sAC-derived cAMP from pigment cells to control late invagination of the hindgut. Little is known about the ancestral functions of ABCC5/MRP5 transporters, and this study reveals a novel role for these proteins in mesoderm-endoderm signaling during embryogenesis.

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“…Extracellular adenosine, in turn, can interact with one or more G-protein-coupled P1 receptors [18] or can be taken back up into cells via ENT (equilibrative nucleoside transporter [19]) to undergo metabolic fates that include the synthesis of ATP. One consequence of the activation of P1 (and certain P2Y) receptors is a change in cellular levels of cAMP, which can exit cells by certain multidrug resistant proteins (MRPs 4 and 5; [20]). The conversion of extracellular cAMP to AMP by D. discoidium occurs via extracellular phosphodiesterases [21].…”

Section: Introductionmentioning

confidence: 99%

New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors

Corriden

Insel

2012

Purinergic Signalling

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The directional movement of cells can be regulated by ATP, certain other nucleotides (e.g., ADP, UTP), and adenosine. Such regulation occurs for cells that are "professional phagocytes" (e.g., neutrophils, macrophages, certain lymphocytes, and microglia) and that undergo directional migration and subsequent phagocytosis. Numerous other cell types (e.g., fibroblasts, endothelial cells, neurons, and keratinocytes) also change motility and migration in response to ATP, other nucleotides, and adenosine. In this article, we review how nucleotides and adenosine modulate chemotaxis and motility and highlight the importance of nucleotide-and adenosine-regulated cell migration in several cell types: neutrophils, microglia, endothelial cells, and cancer cells. We also discuss difficulties in conducting experiments and drawing conclusions regarding the ability of nucleotides and adenosine to modulate the migration of professional and non-professional phagocytes.

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Cellular Efflux of cAMP and cGMP - A Question about Selectivity

Abstract: The present paper reviews and discusses selectivity of ABCC4 (MRP4), ABCC5 (MRP5) and ABCC11 (MRP8) as cellular efflux pumps for cAMP and cGMP. These transporters are potential drug targets for selective modulation of cyclic nucleotide action.

Cited by 38 publications

References 51 publications

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors

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Cellular Efflux of cAMP and cGMP - A Question about Selectivity

Abstract: The present paper reviews and discusses selectivity of ABCC4 (MRP4), ABCC5 (MRP5) and ABCC11 (MRP8) as cellular efflux pumps for cAMP and cGMP. These transporters are potential drug targets for selective modulation of cyclic nucleotide action.

Cited by 38 publications

References 51 publications

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na+ Self-Inhibition of Epithelial Na+ Channels

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na+ Self-Inhibition of Epithelial Na+ Channels

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors

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Product

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8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels