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Constitutively Active Gq Impairs Gonadotropin-Releasing Hormone-Induced Intracellular Signaling and Luteinizing Hormone Secretion in LßT2 Cells

Department of Medicine (F.L., M.S.R., N.J.G.W.), and the University of California San Diego (UCSD) Cancer Center (N.J.G.W.), University of California, San Diego, California 92093; and the Medical Research Service (D.A.A., N.J.G.W.), Veterans Affairs San Diego Healthcare System, San Diego California 92161

Address all correspondence and requests for reprints to: Dr. Nicholas J. G. Webster, Department of Medicine 0673, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673. E-mail: nwebster{at}ucsd.edu.

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)ß1, a target of Gq in these cells, but not PLCß3 or PLC1. Downstream of PLCß1, 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 LHß proteins, indicating that the novel PKCs signal to the ERK cascade. Despite reductions in PLCß1, 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 LHß synthesis and LH secretion.

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