Abstract
BackgroundThe multixenobiotic resistance system (MXR) allows aquatic organisms to cope with their habitat despite high pollution levels by over-expressing membrane and intracellular transporters, including the P-glycoprotein (Pgp). In mammals transcription of the ABCB1 gene encoding Pgp is under cAMP/PKA-mediated regulation; whether this is true in mollusks is not fully clarified.Methodology/Principal FindingscAMP/PKA regulation and ABCB mRNA expression were assessed in haemocytes from Mediterranean mussels (Mytilus galloprovincialis) exposed in vivo for 1 week to 0.3 ng/L fluoxetine (FX) alone or in combination with 0.3 ng/L propranolol (PROP). FX significantly decreased cAMP levels and PKA activity, and induced ABCB mRNA down-regulation. FX effects were abolished in the presence of PROP. In vitro experiments using haemocytes treated with physiological agonists (noradrenaline and serotonin) and pharmacological modulators (PROP, forskolin, dbcAMP, and H89) of the cAMP/PKA system were performed to obtain clear evidence about the involvement of the signaling pathway in the transcriptional regulation of ABCB. Serotonin (5-HT) decreased cAMP levels, PKA activity and ABCB mRNA expression but increased the mRNA levels for a putative 5-HT1 receptor. Interestingly, 5-HT1 was also over-expressed after in vivo exposures to FX. 5-HT effects were counteracted by PROP. Forskolin and dbcAMP increased PKA activity as well as ABCB mRNA expression; the latter effect was abolished in the presence of the PKA inhibitor H89.ConclusionsThis study provides the first direct evidence for the cAMP/PKA-mediated regulation of ABCB transcription in mussels.
Highlights
Environmental physiologists often link the endogenous processes of organisms with exogenous stimuli affecting them in order to understand the impact of pollution on the broader distributions of populations and species
Haemocytes collected from mussels exposed to FX showed significantly decreased cAMP levels and protein kinase (PKA) activity above control values, and ABCB mRNA down-regulation (Fig. 1)
Haemocytes from control M. galloprovincialis were treated with either noradrenaline (NOR) or serotonin (5-HT) as selective agonists of adrenergic (AR) and 5-HT receptors, respectively
Summary
Environmental physiologists often link the endogenous processes of organisms with exogenous stimuli affecting them in order to understand the impact of pollution on the broader distributions of populations and species. The responses are often behavioral or metabolic, a powerful mechanism employed by these organisms to cope with environmental challenges is the regulation of genes and proteins related to cytoprotection. These include the multixenobiotic resistance system (MXR), which prevents the cellular accumulation of potentially harmful xenobiotics by active export from the cell of parental or metabolized forms of the compounds. The multixenobiotic resistance system (MXR) allows aquatic organisms to cope with their habitat despite high pollution levels by over-expressing membrane and intracellular transporters, including the P-glycoprotein (Pgp). In mammals transcription of the ABCB1 gene encoding Pgp is under cAMP/PKA-mediated regulation; whether this is true in mollusks is not fully clarified
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