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CART peptides are important neurotransmitters, but little is known about their receptors or signaling pathways in cells. In this study we describe the effects of CART 55–102 on the stimulation of extracellular signal-related kinase (ERK) in a pituitary-derived cell line. CART 55–102 treatment resulted in markedly enhanced ERK phosphorylation in AtT20 and GH3 cells, but had no significant effect on ERK phosphorylation levels in a variety of other cell types that were examined. The peptide activated ERK1 and 2 in AtT20 cells in a dose- and time-dependent manner, but an inactive peptide, CART 1–27, had no effect. U0126, an inhibitor of the MEK kinases, blocked the CART-stimulated activation of ERKs. ERK activation was also attenuated by pertussis toxin pre-treatment, but not by genistein, suggesting a Gi/o-dependent mechanism. Overall, these data strongly support the existence of a specific receptor for CART …