Trends in Cellular Signaling Editors: Dave E. Caplin Chapter 1 FMLP-OME ANALOGUES TRIGGER SPECIFIC SIGNALLING P ATHWAYS IN THE PHYSIOLOGICAL FUNCTIONS OF HUMAN NEUTROPHILS Susanna Spisani 1, * , and Rita Selvatici 2 1 Dipartimento di Biochimica e Biologia Molecolare, Università degli Studi di Ferrara, 44100 Ferrara, Italy, 2 Dipartimento di Medicina Sperimentale e Diagnostica, Sezione Genetica Medica, Università degli Studi di Ferrara, 44100 Ferrara, Italy. ABSTRACT Human neutrophils are phagocytic cells involved in host defence mechanisms against bacterial infections. It has been demonstrated that small formyl-peptide derivatives, obtained as bacterial metabolites or derived from disrupted mitochondria, can be potent chemoattractants for phagocytes. for-Met-Leu-Phe (fMLP), together with its synthetic methyl ester derivative for-Met-Leu-Phe-OMe (fMLP-OMe), is used as a model chemoattractant due to its highly effective ability to activate all physiological functions of neutrophils through binding with specific G-protein coupled receptors (FPR) located on the neutrophil membrane. The interaction of fMLP with its receptor expressed on neutrophils triggers multiple second messengers through the activation of phospholipase C (PLC), PLD and PLA 2 and rapidly stimulates phosphatidylinositol-3-kinase (PI3-K), as well as activating tyrosine phosphorylation. An increase in intracellular levels of cyclic AMP (cAMP) and the involvement of kinases, such as protein kinase C (PKC), mitogen-activated protein kinases (MAPKs) [Jun N-terminal kinases (JNK), p38 and extracellular response kinases 1 and 2 (ERK1/2)], has also been demonstrated. The activation of these transduction pathways is known to be responsible for various biochemical responses which contribute to the physiological defence against bacterial infections and cell disruption. In fact, it has long been known that the transduction pathway underlying the chemotactic response is different from those responsible for * Correspondence concerning this article should be addressed to Susanna Spisani, Dipartimento di Biochimica e Biologia Molecolare, Via L. Borsari 46, Università degli Studi di Ferrara, 44100 Ferrara, Italy, tel. +39- 0532291424, fax +39-0532202723; e-mail: sps@unife.it.