The cyclic AMP (cAMP)-dependent signaling accounts for the control of cellular cascades involved in many physiological functions, and a wealth of information is available on the cAMP system operating in mammalian cells. cAMP has a central role also in invertebrate physiology, although scarce information are available regarding the structural and operational characteristics of the main actors regulating cAMP functions in invertebrate species. In this study, modulation of cAMP signaling was analysed in haemocyte cells from the marine bivalve Mytilus galloprovincialis exposed in vitro to selected agonists and antagonists of adrenergic and serotoninergic (5-HT) pathways. Although noradrenaline is the main catecholamine in mussels, it was ineffective on haemocyte cAMP levels. Differently, 5-HT decreased cAMP levels and protein kinase A activity; these effects were fully antagonized by PROP. Real time PCR analyses revealed that 5-HT also induced the up-regulation of a mussel 5-HT receptor structurally homologous to the mammalian 5-HT1 negatively coupled to the formation of cAMP. Finally, 5-HT also induced down regulation of ABCB1 gene expression, which vice versa is increased by forskolin. On the whole, data reported indicate that 5-HT interacts with a receptor negatively coupled to the cAMP system present in mussel haemocytes, and modulates expression of genes coding for the receptor itself and for a membrane transporter.