Insights into the regulation of the MXR response in haemocytes of the Mediterranean mussel (Mytilus galloprovincialis).
This study investigated functional and transcriptional modulation of the Multixenobiotic resistance (MXR) system as a cytoprotective mechanism contributing to the physiological chemoresistance of haemocytes in the Mediterranean mussel. Basal transport activity was assessed using the model substrate rhodamine 123 and specific inhibitors for the MXR-related transporters P-glycoprotein (ABCB mRNA) and Multidrug resistance-related protein (ABCC mRNA). Results showed that MXR activity in mussel haemocytes was mainly supported by the Mrp-mediated efflux. In agreement, ABCC was expressed at higher levels than ABCB. Activation of the cyclic-AMP (cAMP) dependent protein kinase A (PKA) resulted in increased rhodamine efflux, which was counteracted by the selective PKA inhibitor H89. Although serotonin, a physiological modulator of cAMP/PKA signaling and ABCB transcription in haemocytes, did not affect basal MXR transport, the environmental pharmaceuticals fluoxetine, propranolol, and carbamazepine, which interact in different ways with the adrenergic and serotoninergic pathways, were showed to act as modulators and substrates of MXR-related transporters and to affect cell viability. While the increased MXR activity may have lowered the cytotoxic effects of propranolol and carbamazepine, the lack of MXR efflux induction by fluoxetine may play a role in the observed cytotoxicity of the compound.
Department of Biological, Geological and Environmental Sciences, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy; Interdepartment Centre for Environmental Sciences Research, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy. Electronic address: silvia.franzellitti@unibo.it.
Silvia
S
Franzellitti
Department of Biological, Geological and Environmental Sciences, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy; Interdepartment Centre for Environmental Sciences Research, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy.
Teresa
T
Striano
Department of Biological, Geological and Environmental Sciences, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy; Interdepartment Centre for Environmental Sciences Research, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy.
Paola
P
Valbonesi
Department of Biological, Geological and Environmental Sciences, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy; Interdepartment Centre for Environmental Sciences Research, University of Bologna, via S. Alberto 163, 48123, Ravenna, Italy.
Elena
E
Fabbri
D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D006434:Hemocytes / Q000187:drug effects* / Q000378:metabolism; D049878:Mytilus / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D012333:RNA, Messenger; D014874:Water Pollutants, Chemical
ABC transporter; ABCB transcription; ABCC transcription; Adrenergic signaling; Cell signaling; Haemocyte physiology; Marine mussels; Multidrug resistance-related protein; P-glycoprotein; Serotonergic signaling