Pharmacological Characterization of the Receptor Mediating the Anorexigenic Action of the Octadecaneuropeptide: Evidence for an Endozepinergic Tone Regulating Food Intake

International audiencePeptides of the endozepine family, including diazepam-binding inhibitor, the triakontatetraneuropeptide, and the octadecaneuropeptide (ODN), act through three types of receptors, that is, central-type benzodiazepine receptors (CBR), peripheral-type (mitochondrial) benzodiazepine receptors (PBR) and a metabotropic receptor positively coupled to phospholipase C via a pertussis toxin-sensitive G protein. We have previously reported that ODN exerts a potent anorexigenic effect in rat and we have found that the action of ODN is not affected by the mixed CBR/PBR agonist diazepam. In the present report, we have tested the possible involvement of the metabotropic receptor in the anorexigenic activity of ODN. Intracerebroventricular administration of the C-terminal octapeptide (OP) and its head-to-tail cyclic analog cyclo(1-8)OP (cOP) at a dose of 100 ng mimicked the inhibitory effect of ODN on food intake in food-deprived mice. The specific CBR antagonist flumazenil and the PBR antagonist PK11195 did not prevent the effect of ODN, OP, and cOP on food consumption. In contrast, the selective metabotropic endozepine receptor antagonist cyclo(1-8)[DLeu(5)]OP (100-1000 ng; cDLOP) suppressed the anorexigenic effect of ODN, OP, and cOP. At the highest concentration tested (1000 ng), cDLOP provoked by itself a significant increase in food intake. Taken together, the present results indicate that the anorexigenic effect of ODN and OP is mediated through activation of the metabotropic receptor recently characterized in astrocytes. The data also suggest that endogenous ODN, acting via this receptor, exerts an inhibitory tone on feeding behavior

Hemopressin and Other Bioactive Peptides from Cytosolic Proteins: Are These Non-Classical Neuropeptides?

Peptides perform many roles in cell–cell signaling; examples include neuropeptides, hormones, and growth factors. Although the vast majority of known neuropeptides are produced in the secretory pathway, a number of bioactive peptides are derived from cytosolic proteins. For example, the hemopressins are a family of peptides derived from alpha and beta hemoglobin which bind to the CB1 cannabinoid receptor, functioning as agonists or antagonists/inverse agonists depending on the size of the peptide. However, the finding that peptides derived from cytosolic proteins can affect receptors does not prove that these peptides are true endogenous signaling molecules. In order for the hemopressins and other peptides derived from cytosolic proteins to be considered neuropeptide-like signaling molecules, they must be synthesized in brain, they must be secreted in levels sufficient to produce effects, and either their synthesis or secretion should be regulated. If these criteria are met, we propose the name “non-classical neuropeptide” for this category of cytosolic bioactive peptide. This would be analogous to the non-classical neurotransmitters, such as nitric oxide and anandamide, which are not stored in secretory vesicles and released upon stimulation but are synthesized upon stimulation and constitutively released. We review some examples of cytosolic peptides from various protein precursors, describe potential mechanisms of their biosynthesis and secretion, and discuss the possibility that these peptides are signaling molecules in the brain, focusing on the criteria that these peptides would have to fill in order to be considered non-classical neuropeptides