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      Constitutively active Gq impairs gonadotropin-releasing hormone-induced intracellular signaling and luteinizing hormone secretion in LbetaT2 cells.

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          Abstract

          Chronic GnRH treatment causes homologous desensitization by reducing GnRH receptor and Gq/11 expression and by down-regulating protein kinase C (PKC), cAMP, and calcium-dependent signaling. It also causes heterologous desensitization of other Gq-coupled receptors, but the mechanisms involved remain elusive. In this study, we investigated the effect of constitutive activation of Gq signaling on GnRH-induced signaling and LH secretion. We show that adenoviral expression of a constitutively active mutant Gq(Q209L) results in a state of GnRH resistance but does not alter GnRH receptor expression. We observed that Gq(Q209L) reduced expression of phospholipase C (PLC)beta1, a target of Gq in these cells, but not PLCbeta3 or PLCgamma1. Downstream of PLCbeta1, expression of novel PKC isoforms (delta and epsilon) was reduced. Adenoviral expression of a kinase-inactive, dominant-negative version of PKCdelta impaired GnRH activation of ERK, but not induction of c-Fos and LHbeta proteins, indicating that the novel PKCs signal to the ERK cascade. Despite reductions in PLCbeta1, calcium responses to GnRH were elevated in Gq(Q209L)-infected cells due to increased calcium influx through L-type calcium channels. Paradoxically, downstream calcium-dependent signaling and LH secretion were impaired. Taken together, these data demonstrate that prolonged activation of the Gq pathway desensitizes GnRH-induced signaling by selectively down-regulating the PLC-PKC-Ca2+ pathway, leading to reduced LHbeta synthesis and LH secretion.

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          Author and article information

          Journal
          Mol Endocrinol
          Molecular endocrinology (Baltimore, Md.)
          The Endocrine Society
          0888-8809
          0888-8809
          Aug 2005
          : 19
          : 8
          Affiliations
          [1 ] Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
          Article
          me.2004-0145
          10.1210/me.2004-0145
          15878957
          c145456f-d6f8-47bd-a601-49e42f0db02e
          History

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