Novel endogenous peptide agonists of cannabinoid receptors

Hemopressin (Hp), a 9-residue alpha-hemoglobin-derived peptide, was previously reported to function as a CB(1) cannabinoid receptor antagonist (1). In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hp alpha) or two (VD-Hp alpha) additional amino acids, as well as a beta-hemoglobinderived peptide with sequence similarity to that of hemopressin (VD-Hp beta). Characterization of the alpha-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB(1) cannabinoid receptor antagonist, both RVD-Hp alpha and VD-Hp alpha function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca(2+) indicate that these peptides activate a signal transduction pathway distinct from that activated by the endo-cannabinoid, 2-arachidonoylglycerol, or the classic CB(1) agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB(1) receptor is involved in the integration of signals from both lipid-and peptide-derived signaling molecules.-Gomes, I., Grushko, J. S., Golebiewska, U., Hoogendoorn, S., Gupta, A., Heimann, A. S., Ferro, E. S., Scarlata, S., Fricker, L. D., Devi, L. A. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J. 23, 3020-3029 (2009). www.fasebj.orgNIH[DA019521]U.S. National Institutes of Health (NIH)U.S. National Institutes of Health (NIH)NIH[GM05313]NIH[GM071558]U.S. National Institutes of Health (NIH)NIH[DA04494]U.S. National Institutes of Health (NIH)U.S. National Institutes of Health (NIH)NIH[DK51271]Zwanenberg Foundation FellowshipZwanenberg Foundation FellowshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[04/04933-2]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[04/14258-0]CNPq Conselho Nacional de Desenvolvimento Cientifico e TecnologicoConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq