THE CLONED MU-RECEPTORS, DELTA-RECEPTORS AND KAPPA-RECEPTORS AND THEIR ENDOGENOUS LIGANDS - EVIDENCE FOR 2 OPIOID PEPTIDE RECOGNITION CORES

The opioid peptides are derived from three prohormone precursors refer red to as proopiomelanocortin (POMC), proenkephalin (ProEnk) and prody norphin (ProDyn). Following specific cleavage, several biologically ac tive peptides are generated that can bind the mu, delta and kappa rece ptors. The present study examines the receptor binding affinities of t he POMC, ProEnk and ProDyn peptides to the cloned mu, delta and kappa receptors expressed transiently in transfected COS-1 cells. Consistent with previous findings using brain homogenates, competition studies d emonstrate that no opioid peptide family can be exclusively associated with a specific opioid receptor type. Short ProEnk peptides, such as Leu- and Met-enkephalin are selective for delta, but C-terminally exte nded peptides such as Met-Enk-Arg-Gly-Leu and Met-Enk-Arg-Phe have a h igh affinity to mu, delta and kappa. Similarly, Peptide E, the BAM pep tides, and metorphamide have a high affinity for all three opioid rece ptor types. While dynorphin A peptides and alpha- and beta-neoendorphi n have a preference for kappa, they also bind the cloned delta and mu receptors. Our findings do not easily fit a simple 'message-address' m odel where the Try-Gly-Gly-Phe core is extended and this gradually alt ers selectivity. Rather, the pattern appears more discontinuous, and w ould fit better with the idea of two similar but distinct cores; a Tyr -Gly-Gly-Phe Met- or Leu core that is necessary and sufficient for mu and delta but not kappa and a Tyr-Gly-Gly-Phe-Met or Leu core with an Arg-X extension that is equally necessary and sufficient for kappa.