The role of calcium and cAMP in the mechanism of action of two melanocortins: alpha MSH and the ACTH4-9 analogue Org 2766.

Melanocortins accelerate functional recovery after nerve crush and enhance 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 adrenocorticotropin4-9 analogue Org 2766 on second messengers in cultures of spinal cord (SC), dorsal root ganglion (DRG) and Schwann cells. alpha MSH (10 microM) enhanced the forskolin-induced cAMP production in SC- (45%) and in DRG-cells (35%). Org 2766 (1 microM) 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-measurements of all cell types, however, Ca(2+)-imaging revealed an infrequent occurrence of large [Ca2+]i-elevations in individual SC-neurons. The results indicate that SC- and DRG-cells are targets for both peptides, while Schwann cells are not or exploit different pathways. We observed for alpha MSH that cAMP production always coincides with outgrowth stimulation, whereas for Org 2766 cAMP production and outgrowth stimulation appear not causally related. These differences in second messenger stimulation could be explained by receptor heterogeneity. We suggest that alpha MSH and Org 2766 act through different receptors, each with its own signalling pathways.