cAMP efflux from human trophoblast cell lines: a role for multidrug resistance protein (MRP)1 transporter

Abstract

Cyclic adenosine 3'-5'-monophosphate (cAMP) is a second messenger, which exerts an important role in the control of human first-trimester trophoblast functions. In the present study we demonstrate the existence of a mechanism that is able to extrude cAMP from trophoblast-derived cell lines, and show evidence indicating the involvement of multidrug resistance protein (MRP) 1, a transporter belonging to the ATP-binding cassette family, in cAMP egress. MRP1 is expressed in trophoblast cell lines and cAMP efflux is highly reduced by the MRP1 inhibitor, MK-571. In addition, interleukin-1beta and estrone are able to enhance MRP1 gene expression and influence extracellular cAMP concentration. The occurrence of a MRP1-dependent cAMP efflux is also shown in human first-trimester placenta explants. Extracellular cAMP could represent a source for adenosine formation, which in turn could regulate cAMP-dependent responses in placental tissue. Evidence is provided that adenosine receptor subtypes are present and functional in human trophoblast-derived cells. A role for cAMP egress mechanism in the fine modulation of the nucleotide homeostasis is therefore suggested.

Inactivation of Multidrug Resistance Proteins Disrupts Both Cellular Extrusion and Intracellular Degradation of cAMP

“…1 and 2) reveals critical differences between their respective kinetics. Intracellular cAMP levels quickly plateau and subsequently return to basal levels, whereas extracellular cAMP levels continue to increase over extended time periods, a pattern that has also been observed in many other cell models (Penit et al, 1974;Doore et al, 1975;Brunton and Mayer, 1979;Hamet et al, 1989;Andric et al, 2006;Biondi et al, 2010). The different patterns of cAMP accumulation result primarily from differences in the efficiency of cAMP degradation.…”

Contribution of the Extracellular cAMP-Adenosine Pathway to Dual Coupling of β2-Adrenoceptors to Gsand GiProteins in Mouse Skeletal Muscle

“…In fact, it is important to emphasize that efflux of cAMP/ cGMP seems to be a widespread signaling mechanism (Hofer and Lefkimmiatis, 2007;Sager and Ravna, 2009) reported in vascular smooth muscle cells (Dubey et al, 1996), cardiac fibroblasts (Dubey et al, 2001), oviduct cells (Cometti et al, 2003), kidney (Jackson and Raghvendra, 2004;Dubey et al, 2010), adipose tissue (Strouch et al, 2005) gastrointestinal tract (Giron et al, 2008), human placenta explants (Biondi et al, 2010), astrocytes, and microglial cells (Verrier et al, 2011). Thus, the extracellular cAMP-adenosine pathway may represent a general autocrine and/or paracrine mechanism that indirectly modulates the signaling triggered by distinct receptors coupled to G s proteins, qualifying cyclic nucleotides as extracellular third messengers, and the extracellular cAMP-adenosine signaling pathway as a potential pharmacological target for therapeutic intervention.…”

Placental control of drug delivery

“…This protein is involved in the transport of both endogenous and exogenous compounds [48]. Cyclic adenosine monophosphate (cAMP) is a substrate of MRP1, and is involved in certain syncytiotrophoblast functions [92]. Interestingly, expression of MRP1 in immortalized placental trophoblast cells was shown to be modulated by interleukin-1β and estrone [92].…”

“…Cyclic adenosine monophosphate (cAMP) is a substrate of MRP1, and is involved in certain syncytiotrophoblast functions [92]. Interestingly, expression of MRP1 in immortalized placental trophoblast cells was shown to be modulated by interleukin-1β and estrone [92]. It was shown that MRP1 is also partially responsible for the transport of methyl mercury to the fetal circulation, which explains the higher levels of methyl mercury in umbilical cord blood in comparison to maternal blood [93].…”

“…It was shown that MRP1 is also partially responsible for the transport of methyl mercury to the fetal circulation, which explains the higher levels of methyl mercury in umbilical cord blood in comparison to maternal blood [93]. The position of MRP1 in the syncytiotrophoblast suggests that MRP1 may not function as a component of the placental barrier, but may rather be involved in other physiological and developmental functions not yet fully understood [92,94]. Transport by MRP1 of estrogen sulfates does appear to be enhanced by reduced glutathione, but this functionality and its relevance in placental tissue is not yet known [95].…”