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Submitted on April 8, 2004
Accepted on April 28, 2005
T2 cells
Department of Medicine, and the UCSD Cancer Center, University of California, San Diego, CA 92093 and the Medical Research Service, VA San Diego Healthcare System, San Diego CA 92161
* To whom correspondence should be addressed. E-mail: nwebster{at}ucsd.edu.
Chronic GnRH treatment causes homologous desensitization by reducing GnRH receptor, Gq/11 expression, and by down-regulating 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 PLC
1, a target of Gq in these cells, but not PLC3 or PLC
1. Downstream of PLC1, expression of novel PKC isoforms (
and 
) was reduced. Adenoviral expression of a kinase-inactive, dominant-negative version of PKC impaired GnRH-activation of ERK, but not induction of c-Fos and LH proteins, indicating that the novel PKCs signal to the ERK cascade. Despite reductions in PLC1, 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 LH synthesis and LH secretion.
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