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Endocrinology Vol. 138, No. 6 2259-2266
Copyright © 1997 by The Endocrine Society

ARTICLES

Gonadotropin-Releasing Hormone and Pituitary Adenylate Cyclase-Activating Polypeptide Affect Levels of Cyclic Adenosine 3',5'-Monophosphate-Dependent Protein Kinase A (PKA) Subunits in the Clonal Gonadotrope {alpha}T3–1 Cells: Evidence for Cross-Talk between PKA and Protein Kinase C Pathways1

Ghislaine Garrel, Craig A. McArdle, Brian A. Hemmings and Raymond Counis

Endocrinologie Cellulaire et Moléculaire de la Reproduction, Université Pierre et Marie Curie, Unité de Recherche Associeé au Centre National de la Recherche Scientifique (URA CNRS) 1449, Paris, France; Department of Medicine, University of Bristol, Dorothy Crowfoot Hodgkins Laboratories, BS2 8HW Bristol, United Kingdom; and Friedrich Miescher Institute, 4002 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. Raymond Counis, Endocrinologie cellulaire et Moléculaire de la Reproduction, Université Pierre et Marie Curie, Unité de Recherche Associeé au Centre National de la Recherche Scientifique (URA CNRS) 1449, Case 244, 75252 Paris cedex 05, France. E-mail: Raymond.counis{at}snv.jussieu.fr

We have shown previously that protein kinase A (PKA) subunit levels are regulated by activation of PKA or protein kinase C (PKC) in anterior pituitary cells. GnRH also influenced PKA subunit levels, suggesting that hormonal regulation occurs in gonadotrophs, and therefore, we have reexamined this question using the clonal gonadotrope-derived cell line ({alpha}T3–1 cells). Western blot analysis, using specific immunoaffinity purified immunoglobulins, revealed expression of catalytic (Cat) and regulatory type I (RI) and type II (RII) subunits of PKA in these cells. Activation of adenylyl cyclase (AC) with forskolin, or of PKC with tetradecanoyl phorbol acetate (TPA), caused a rapid (detectable at 0.5–1 h) and concentration-dependent loss of all PKA subunits. Forskolin (10–100 µM) reduced Cat and RI by 60% and RII by 30%, whereas TPA (0.1–1 µM) reduced Cat and RII by 50% and RI by 40%. Simultaneous activation of PKA and PKC caused the expected dose-dependent reductions in Cat, and the effects of forskolin or TPA were nearly additive. RI and RII were reduced similarly by 10 nM TPA, whereas 100 nM TPA tended to prevent the reduction of RI or RII caused by forskolin. GnRH, which activates phosphoinositidase C and not AC in these cells, caused a clear loss of Cat or RII at all concentrations tested and of RI at 0.1 nM. Pituitary adenylate cyclase-activating polypeptide 38, which acts via PVR-1 receptors to stimulate both phosphoinositidase C and AC in these cells, also caused a clear dose-dependent decrease in Cat, RI, and RII, although higher concentrations were needed for the latter effects. Together, the data demonstrate that catalytic and regulatory subunits of PKA are subject to both hormonal and receptor-independent regulation in {alpha}T3–1 cells, reinforcing the possibility that such effects occur in nonimmortalized gonadotropes. Whereas the effects of PKA activators very likely involve proteolytic degradation of the dissociated PKA holoenzyme, the effects of TPA and GnRH occur in the absence of cAMP elevation by unknown mechanisms. Whatever the mechanisms involved, the data reveal a mechanism for cross-talk between phosphoinositidase C and AC-mediated hormonal signals, in which PKC activation seems to play a pivotal role.




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