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Submitted on January 27, 2004
Accepted on March 22, 2004
Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol (CJC, LDG, KRS, ARF and CAM), Department of Pharmacology, University of Bristol (EK and A-L M) and University of California, San Fransisco (JNH).
* To whom correspondence should be addressed. E-mail: craig.mcardle{at}bris.ac.uk.
Desensitization and internalization of GPCRs can be mediated by phosphorylation within the C-terminal tail, facilitating 
-arrestin binding and targeting the receptor for internalization. Type II gonadotropin-releasing hormone receptors (GnRH-Rs) show such regulation but type I GnRH-Rs lack C-tails and are not rapidly desensitized or internalized. Here we show contrasting susceptibility of type I (human and sheep) and II (Xenopus) GnRH-Rs to regulation by PKC. When human (h) or Xenopus (X) GnRH-Rs were expressed using recombinant adenovirus, PKC activation increased radioligand binding to XGnRH-Rs but not to hGnRH-Rs. A dominant-negative dynamin mutant (K44A) inhibited internalization of XGnRH-Rs (but not hGnRH-Rs) without influencing PKC regulation of XGnRH-R binding. PKC activation increased the affinity of XGnRH-Rs for the type II GnRH ligand and increased effects of low concentrations of GnRH-II on the [Ca2+]i but had no effect on type I ligand binding to hGnRH-Rs, sGnRH-Rs or XGnRH-Rs or to chimeric receptors with the XGnRH-R C-tail added to a type I receptor. Binding of type II ligand to human or sheep receptors was also unaffected, but was increased in the chimeras. Mutation of both PKC-phosphorylation consensus sites in the XGnRH-R tail did not prevent the PKC-mediated increases in binding or alter agonist-induced translocation of -arrestin2/GFP or inhibition of inositol-phosphate accumulation by -arrestin2/GFP. Thus it appears that there are two distinct active conformations of XGnRH-Rs (differing in affinity for type I and II ligands) and that these cells exhibit a novel form of "inside-out signaling" in which PKC feeds back to influence receptor affinity.
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