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

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...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2005-08, Vol.19 (8), p.2074-2085
Main Authors: Liu, Fujun, Ruiz, Maribeth S, Austin, Darrell A, Webster, Nicholas J G
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Adenoviridae - genetics
Animals
Blotting, Western
Calcium - metabolism
Cytosol - metabolism
Down-Regulation
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases - metabolism
Gonadotropin-Releasing Hormone - metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 - physiology
Isoenzymes - metabolism
Kinetics
Luteinizing Hormone - secretion
Mice
Mutation
Phospholipase C beta
Phosphorylation
Protein Isoforms
Protein Kinase C - metabolism
Proto-Oncogene Proteins c-fos - metabolism
Signal Transduction
Time Factors
Type C Phospholipases - metabolism
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Summary: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.
ISSN:0888-8809