Novel endogenous peptide agonists of cannabinoid receptors

• Published in: The FASEB journal 2009-09, Vol.23 (9), p.3020-3029
• Main Authors: Gomes, Ivone, Grushko, Julia S, Golebiewska, Urszula, Hoogendoorn, Sascha, Gupta, Achla, Heimann, Andrea S, Ferro, Emer S, Scarlata, Suzanne, Fricker, Lloyd D, Devi, Lakshmi A
• Format: Article
• Language: English
• Subjects: analgesia; Brain; Cannabinoid Receptor Agonists; Cell Line; drug abuse; G‐protein‐coupled receptors; Hemoglobins - chemistry; Humans; Lipids; Mitogen-Activated Protein Kinase 3 - metabolism; pain; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptides - chemical synthesis; Peptides - pharmacology; Phosphorylation; Research Communications; Signal Transduction
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.09-132142

Hemopressin (Hp), a 9-residue α-hemoglobin-derived peptide, was previously reported to function as a CB₁ 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-Hpα) or two (VD-Hpα) additional amino acids, as well as a β-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hpβ). Characterization of the α-hemoglobin-derived peptides using binding and functional assays shows that in contrast to Hp, which functions as a CB₁ cannabinoid receptor antagonist, both RVD-Hpα and VD-Hpα function as agonists. Studies examining the increase in the phosphorylation of ERK1/2 levels or release of intracellular Ca²⁺ indicate that these peptides activate a signal transduction pathway distinct from that activated by the endocannabinoid, 2-arachidonoylglycerol, or the classic CB₁ agonist, Hu-210. This finding suggests an additional mode of regulation of endogenous cannabinoid receptor activity. Taken together, these results suggest that the CB₁ 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.