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-Hpalpha) or two (VD-Hpalpha) additional amino acids, as well as a beta-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hpbeta). 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-Hpalpha and VD-Hpalpha 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 endocannabinoid, 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
Ivone
I
Department of Pharmacology and Systems Therapeutics, Mt. Sinai School of Medicine, New York, NY 10029, USA.
Grushko
Julia S
JS
Golebiewska
Urszula
U
Hoogendoorn
Sascha
S
Gupta
Achla
A
Heimann
Andrea S
AS
Ferro
Emer S
ES
Scarlata
Suzanne
S
Fricker
Lloyd D
LD
Devi
Lakshmi A
LA
D001921:Brain; D063386:Cannabinoid Receptor Agonists; D002460:Cell Line; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D008055:Lipids; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation; D015398:Signal Transduction
D063386:Cannabinoid Receptor Agonists; D006454:Hemoglobins; D008055:Lipids; D010446:Peptide Fragments; D010455:Peptides; C473218:hemopressin; D048052:Mitogen-Activated Protein Kinase 3