Prolactin-releasing peptide effects in the rat brain are mediated through the Neuropeptide FF receptor.
Prolactin-releasing peptide (PrRP), an RF amide peptide present in the brain, generates a wide variety of centrally generated autonomic responses, including increases in arterial blood pressure and heart rate. The identity of the receptor mediating the effects of PrRP is unknown. In addition to GPR10, which is its putative endogenous receptor, PrRP demonstrates a high binding affinity for Neuropeptide FF (NPFF) receptors, specifically the NPFF2 receptor. In the present study, we examined whether the central cardiovascular effects of PrRP in the intact animal and its cellular effects on parvocellular paraventricular nucleus (PVN) neurons are mediated via NPFF receptors. In conscious rats, intracerebroventricular (i.c.v.) PrRP caused an increase in arterial blood pressure and heart rate, which was blocked with RF9, a specific NPFF receptor antagonist. These PrRP-evoked cardiovascular effects were preserved in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat strain, in which the GRP10 receptor gene was mutated. In rat brain slices, whole-cell patch clamp recordings of parvocellular paraventricular nucleus neurons show PrRP caused a decrease in evoked and miniature GABAergic inhibitory postsynaptic currents (IPSCs), effects that were antagonized by RF9, but not neuropeptide Y, a putative GPR10 receptor antagonist. The effects of PrRP on IPSCs in OLETF rats were similar to those in wild-type rats. Both in vivo and in vitro data strongly suggest that certain PrRP effects in the brain are expressed via NPFF receptors, probably NPFF2, rather than the GPR10 receptor. These observations may assume clinical relevance as RF amide peptides such NPFF and PrRP become therapeutic targets for a variety of autonomically related disorders.
Ma
Li
L
Department of Medicine (Neurology) and Centre for Neuroscience, University of Alberta, Edmonton, AB, Canada.
MacTavish
David
D
Simonin
Frédéric
F
Bourguignon
Jean-Jacques
JJ
Watanabe
Takeshi
T
Jhamandas
Jack H
JH
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D056690:Prolactin-Releasing Hormone / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D004151:Dipeptides; D009478:Neuropeptide Y; C112345:PRLHR protein, human; D056690:Prolactin-Releasing Hormone; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C508361:adamantylcarbonyl-arginyl-phenylalaninamide; C083929:neuropeptide FF receptor; D005680:gamma-Aminobutyric Acid; D000218:Adamantane