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Regulation of gonadotropin-releasing hormone receptors by protein kinase C: Inside out signalling and evidence for multiple active conformations


Reference:

Caunt, C. J., Hislop, J. N., Kelly, E., Matharu, A. L., Green, L. D., Sedgley, K. R., Finch, A. R. and McArdle, C. A., 2004. Regulation of gonadotropin-releasing hormone receptors by protein kinase C: Inside out signalling and evidence for multiple active conformations. Endocrinology, 145 (8), pp. 3594-3602.

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Official URL:

http://dx.doi.org/10.1210/en.2004-0092

Abstract

Desensitization and internalization of G protein-coupled receptors can be mediated by phosphorylation within the C-terminal tail, facilitating beta-arrestin binding and targeting the receptor for internalization. Type II GnRH 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 protein kinase C (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 beta-arrestin2/green fluorescent protein or inhibition of inositol phosphate accumulation by beta-arrestin2/green fluorescent protein. 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.

Details

Item Type Articles
CreatorsCaunt, C. J., Hislop, J. N., Kelly, E., Matharu, A. L., Green, L. D., Sedgley, K. R., Finch, A. R. and McArdle, C. A.
DOI10.1210/en.2004-0092
DepartmentsFaculty of Science > Biology & Biochemistry
RefereedYes
StatusPublished
ID Code20403

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