Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Authors

Sreenivasan Paruthiyil, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San FranciscoFollow
Mohammed El Majdoubi, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San FranciscoFollow
Marco Conti, Department of Obstetrics and Gynecology, Stanford University, Stanford
Richard I. Weiner, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San FranciscoFollow

Document Type

Article

Source

Proceedings of the National Academy of Sciences of the United States of America

ISSN

1091-6490

Volume

99

Issue

26

First Page

17191

Last Page

17196

Publication Date

2002

Department

Natural Sciences and Mathematics

Abstract

Experiments in the GT1 gonadotropin-releasing hormone (GnRH) cell line have shown that the cAMP signaling pathway plays a central role in regulating the excitability of the cells. Lowering cAMP levels by expressing the constitutively active cAMP-specific phosphodiesterase PDE4D1 in GT1 cells inhibited spontaneous Ca2+ oscillations and intrinsic pulsatile GnRH secretion. To address the role of cAMP levels in endogenous GnRH neurons, we genetically targeted expression of PDE4D1 (P) to GnRH neurons in transgenic rats (R) by using the GnRH gene promoter/enhancer regions (G). Three lines of transgenic rats, GPR-2, -4, and -5, were established. In situ hybridization and RT-PCR studies demonstrated that transgene expression was specifically targeted to GnRH neurons. Decreased fertility was observed in female but not in male rats from all three lines. The mean luteinizing hormone (LH) levels in ovariectomized rats were significantly reduced in the GPR-4 and -5 lines but not in the GPR-2 line. In castrated male and female GPR-4 rats, the LH pulse frequency was dramatically reduced. Six of twelve GPR-4 females studied did not ovulate and had polycystic ovaries. The remaining six females ovulated, but the magnitude of the preovulatory LH surge was inhibited by 63%. These findings support the hypothesis that cAMP signaling may play a central role in regulating excitability of GnRH neurons in vivo. The GPR-4 line of transgenic rats provides a genetic model for the understanding of the role of pulsatile gonadotropin release in follicular development.

Rights

Copyright © 2002 The Author(s)

PubMed ID

12482943

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.