Paradoxical activational effects of a corticotropin-releasing factor-binding protein "ligand inhibitor" in rat brain.
The corticotropin-releasing factor-binding protein is distinct from known corticotropin-releasing factor receptors, but can bind the peptide and neutralize its biological actions. Recent interest has centered about the therapeutic potential of "ligand inhibitors" of binding protein action, synthetic corticotropin-releasing factor fragments which are inactive at corticotropin-releasing factor receptors, but can displace the peptide from the binding protein, thereby increasing levels of free corticotropin-releasing factor. To identify sites of action of such ligands, the distribution of Fos expression seen following intracerebroventricular administration of rat/human corticotropin-releasing factor(6-33) (5-50 microg) was charted in relation to corticotropin-releasing factor-binding protein and receptor expression. It was expected that Fos induction would mimic aspects of the distribution of the two known corticotropin-releasing factor receptors, but the far greater correspondence was seen with that of the binding protein itself. This included neurons in the isocortex, the olfactory system, amygdala and a number of discrete brainstem cell groups; many Fos-immunoreactive neurons in each were found to co-express corticotropin-releasing factor-binding protein messenger RNA. Subsets of activated neurons co-expressed Type 1 corticotropin-releasing factor receptor messenger RNA, though these were largely limited to cell groups that also express the corticotropin-releasing factor-binding protein, and where binding protein immunoreactivity and Type 1 receptor transcripts were found to co-exist. Responsive neurons displaying Type 2 corticotropin-releasing factor receptor message were seen reliably only in the lateral septal nucleus. These findings support only a limited capacity of the ligand inhibitor to activate neurons bearing corticotropin-releasing factor receptors. The more pervasive activation seen among neurons that express the corticotropin-releasing factor-binding protein may be indicative of an unexpected role for this protein in signaling by corticotropin-releasing factor-related peptides.
Chan
R K
RK
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Vale
W W
WW
Sawchenko
P E
PE
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D054832:Urocortins
D002352:Carrier Proteins; D008024:Ligands; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C067133:corticotropin releasing factor-binding protein; D003346:Corticotropin-Releasing Hormone