Abstract
Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) has multiple, but transient, homeostatic functions in the brain. It is hydrolyzed in vitro by pyroglutamyl peptidase II (PPII), a narrow specificity ectoenzyme with a preferential localization in the brain, but evidence that PPII controls TRH communication in the brain in vivo is scarce. We therefore studied in male Wistar rats the distribution of PPII mRNA in the septum and the consequence of PPII inhibition on the analeptic effect of TRH injected into the medial septum. Twelve to 14% of cell profiles expressed PPII mRNA in the medial septum-diagonal band of Broca; in this region the specific activity of PPII was relatively high. Twenty to 35% of PPII mRNA-labeled profiles were positive for TRH-receptor 1 (TRH-R1) mRNA. The intramedial septum injection of TRH reduced, in a dose-dependent manner, the duration of ethanol-induced loss of righting reflex (LORR). Injection of the PPII inhibitor pGlu-Asn-Pro-7-amido-4-methylcoumarin into the medial septum enhanced the effect of TRH. The injection of a phosphinic TRH analog, a higher-affinity inhibitor of PPII, diminished the duration of LORR by itself. In contrast, the intraseptal injection of pGlu-Asp-Pro-NH2, a peptide that did not inhibit PPII activity, or an inhibitor of prolyl oligopeptidase did not change the duration of LORR. We conclude that in the medial septum PPII activity may limit TRH action, presumably by reducing the concentration of TRH in the extracellular fluid around cells coexpressing PPII and TRH-R1.
Footnotes
This work was supported in part by the Consejo Nacional de Ciencia y Tecnología [Grant 61804] (to J.-L.C.); and the Dirección General de Asuntos del Personal Académico of the Universidad Nacional Autónoma de México [Grant IN221109] (to J.-L.C.).
I.L. is a student in the Programa de Posgrado en Ciencias Biológicas de la Universidad Nacional Autónoma de México.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- TRH
- thyrotropin-releasing hormone
- ΨTRH
- pGluΨ[P(O)(OH)]His-Pro-NH2
- TRH-R
- TRH receptor
- aCSF
- artificial cerebrospinal fluid
- DBB
- diagonal band of Broca
- hDBB
- horizontal DBB
- vDBB
- vertical DBB
- DMSO
- dimethyl sulfoxide
- ISH
- in situ hybridization
- LORR
- loss of righting reflex
- MCA
- 7-amido-4-methylcoumarin
- MS
- medial septum
- PCR
- polymerase chain reaction
- POP
- prolyl oligopeptidase
- PPII
- pyroglutamyl peptidase II
- rPPII
- recombinant PPII
- RT
- reverse transcription
- TSH
- thyrotropin
- ZPP
- N-benzyloxycarbonyl prolyl prolinal
- JTP-4819
- ((S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-phenylmethyl)-1-pyrrolidinecarboxamide).
- Received January 20, 2012.
- Accepted April 20, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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