The β-blocker propranolol affects cAMP-dependent signaling and induces the stress response in Mediterranean mussels, Mytilus galloprovincialis.

Show thumbnails in outlineArticle outline is loading... Abstract Keywords 1. Introduction 2. Materials and methods 2.1. Experimental animals and holding conditions 2.2. Test substances 2.3. Experimental setup 2.4. Cyclic AMP-related cascade reactions 2.4.1. Cyclic AMP content 2.4.2. PKA activity 2.4.3. Mussel P-glycoprotein (MgPgp) mRNA expression 2.5. Lysosomal membrane stability (LMS) 2.6. Detoxification enzyme activities 2.7. Statistical analysis 3. Results 3.1. cAMP-related parameters in mussels exposed to l-PROP (Experiment I) 3.2. Sensitivity of cAMP-related parameters to l-PROP exposure (Experiment I) Table 1. 3.3. cAMP-related parameters in mussels exposed to dl-PROP (Experiment II) 3.4. Biomarker responses in mussels exposed to dl-PROP (Experiment II) 3.5. Sensitivity of biomarkers and cAMP-related parameters to dl-PROP exposure (Experiment II) Table 2. 4. Discussion Table 3. Acknowledgements References Aquatic Toxicology Volume 101, Issue 2, 25 January 2011, Pages 299–308 The β-blocker propranolol affects cAMP-dependent signaling and induces the stress response in Mediterranean mussels, Mytilus galloprovincialis Silvia Franzellittia, Sara Burattia, Paola Valbonesia, Antonio Capuzzob, Elena Fabbria, , a University of Bologna, Interdepartment Centre for Research in Environmental Sciences (CIRSA), via S. Alberto 163, 48123 Ravenna, Italy b University of Ferrara, Department of Biology and Evolution, via Borsari 46, 44100 Ferrara, Italy Received 20 July 2010. Revised 23 September 2010. Accepted 3 November 2010. Available online 11 November 2010. http://dx.doi.org/10.1016/j.aquatox.2010.11.001, How to Cite or Link Using DOIPermissions & Reprints -------------------------------------------------------------------------------- Widespread occurrence of pharmaceuticals is reported in aquatic systems, posing concerns for the health of aquatic wildlife and a theoretical risk to humans. A recent concept was developed for the identification of highly active compounds amongst the environmental pharmaceuticals, based on their mode of action, the homology between human targets and possible targets in the environment, and the importance of the affected pathway for the target species. In line with this approach, this study investigated whether propranolol (PROP) affects the cAMP-dependent pathway in Mediterranean mussels, Mytilus galloprovincialis. PROP is a prototypical β-adrenoceptor antagonist, and these receptors exist in bivalves and show gross pharmacological properties similar to their mammalian counterparts. PROP also acts as a 5-HT1 receptor antagonist, which is the sole 5-HT receptor reported in bivalves to date. Importantly, β-adrenoceptor and 5HT-1 receptor subtypes are positively and negatively coupled to cAMP-mediated signaling, respectively. PROP was administered as either l-PROP or dl-PROP. A wide range of concentrations was tested including low (0.3, 3 and 30 ng/L) and high (300 ng/L) environmental ranges, and a concentration 5-fold above the maximum reported environmental level (30,000 ng/L). After a 7-day exposure, mussel cAMP levels and PKA activities were significantly reduced in digestive gland, increased in mantle/gonads and unaffected in gills. Similar patterns were observed for the mRNA expression of the ABCB1 gene encoding the membrane transporter P-glycoprotein, hypothesised to be under PKA modulation. The effects on the digestive gland are consistent with PROP blocking β-adrenoceptors. The observed increased cAMP levels in the mantle/gonad tissue support PROP blocking 5-HT1 receptors. Catalase and glutathione-S tranferase were differently affected by PROP in the two tissues. Mussel haemocyte lysosome membrane stability, a sensitive biomarker of animal health status, was concentration-dependently reduced following PROP exposure. Our observations provide evidence for PROP affecting cell signaling in M. galloprovincialis. Moreover, the chemical interacts with specific and evolutionally conserved biochemical pathways for which it was designed. The mode of action of PROP in mussels is related with its therapeutic properties in humans, based upon these conserved human targets. It also induced a stress response, and all these effects were displayed at the lowest concentrations teste