Novel endogenous peptide agonists of cannabinoid receptors

Ivone Gomes, Julia S. Grushko, Urszula Golebiewska, Sascha Hoogendoorn, Achla Gupta, Andrea S. Heimann, Emer S. Ferro, Suzanne Scarlata, Lloyd D. Fricker, Lakshmi A. Devi

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3020-3029
Number of pages10
JournalFASEB Journal
Issue number9
StatePublished - Sep 2009


  • Analgesia
  • Drug abuse
  • G-protein-coupled receptors
  • Pain

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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