THE ROLE OF CALCIUM AND CAMP IN THE MECHANISM OF ACTION OF 2 MELANOCORTINS - ALPHA-MSH AND THE ACTH(4-9) ANALOG ORG-2766

Melanocortins accelerate functional recovery after nerve crush and enh ance neurite outgrowth in vitro. To get more insight in the mechanism of action of melanocortins, we studied the effects of two neurotrophic peptides: alpha-melanocyte-stimulating hormone (alpha MSH) and an adr enocorticotropin(4-9) analogue Org 2766 on second messengers in cultur es of spinal cord (SC), dorsal root ganglion (DRG) and Schwann cells. alpha MSH (10 mu M) enhanced the forskolin-induced cAMP production in SC-(45%) and in DRG-cells (35%). Org 2766 (1 mu M) induced an increase in cAMP only in SC-cells (39%). The peptides did not affect the cAMP levels in Schwann cells. Neither peptide evoked significant changes in the intracellular free calcium concentration ([Ca2+](i)) in batch-mea surements of all cell types, however, Ca2+-imaging revealed an infrequ ent occurrence of large [Ca2+](i)-elevations in individual SC-neurons. The results indicate that SC- and DRG-cells are targets for both pept ides, while Schwann cells are not or exploit different pathways. We ob served for alpha MSH that cAMP production always coincides with outgro wth stimulation, whereas for Org 2766 cAMP production and outgrowth st imulation appear not causally related. These differences in second mes senger stimulation could be explained by receptor heterogeneity. We su ggest that alpha MSH and Org 2766 act through different receptors, eac h with its own signalling pathways.