Opioid receptors activate extracellular signal-regulated MAPKs in a receptor tyrosine kinase independent manner

Activation of opioid receptors results in the phosphorylation of two isoforms of extracellular signal-regulated kinases (ERK1/2). While this mechanism is commonly accepted, the path of intracellular signaling leading to the activation of ERK/MAP kinases remained under discussion. A major issue relates to the question whether receptor tyrosine kinases (RTKs), e.g. the epidermal growth factor receptors (EGFRs), mediate opioid receptor-induced phosphorylation of ERKs. For identification of EGFR-related mechanisms a highly selective inhibitor of RTK transactivation, tyrphostin (AG 1478), has been employed during the past, and inhibition of ERK phosphorylation by tyrphostin has been associated with the involvement of RTKs. The present study examines in HEK 293 cells and others the role of RTKs in opioid receptor-evoked activation of ERKs. The experimental techniques employed to control the individual receptor types of the EGFR family were their blockade by tyrphostin, anti-phospho-EGFR-antibodies, anti-EGFR-antibodies, receptor desensitization and EGFR-siRNAs. The results let us conclude that G protein-coupled opioid receptors do not require transactivation of receptors of the EGFR family to phosphorylate ERK/MAP kinases.