Regulatory Processes Governing the Cell Surface Expression of LH and FSH Receptors - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 108

Chapter 7
Regulatory Processes Governing the Cell
Surface Expression of LH and FSH Receptors
Deborah L. Segaloff
Contents
7.1 Introduction..................................................................................................................... 114
7.2 Synthesis of the Gonadotropin Receptors....................................................................... 115
7.3 Fate of Misfolded Mutants of the Gonadotropin Receptors ........................................... 116
7.4 Homo-Dimerization/Oligomerization of the Gonadotropin Receptors .......................... 118
7.5 Ramifications of Gonadotropin Receptor Dimerization ................................................. 121
7.5.1 Effects on Cell Surface Expression..................................................................... 121
7.5.2 Effects on Signaling Independent of Receptor Cell Surface Expression............ 122
7.6 Conclusion ...................................................................................................................... 124
References ................................................................................................................................ 124
Abstract The LH receptor (LHR) and FSH receptor (FSHR), collectively termed
the gonadotropin receptors, are members of the Family A of GPCRs. The gonado-
tropin receptors each contain N-linked carbohydrates that are not directly involved
in hormone binding, but contribute to the proper folding, and therefore, cell surface
expression of the receptor. Loss-of-function mutations of an LHR or FSHR results
in decreased target cell responsiveness. Most inactivating mutations cause receptor
misfolding, resulting in the retention of the mutant in its immature form in the endo-
plasmic reticulum. A membrane-permeable allosteric agonist of the LHR has been
shown to serve as a pharmacological chaperone for misfolded and intracellularly
retained LHRs by promoting their cell surface expression. Wild-type LHR and
FSHR each form homodimers and heterodimers while in the ER. Therefore, when
wild-type receptor is co-expressed with a misfolded mutant, the misfolded receptor
dimerizes with immature wild-type receptor in the ER, causing a dominant-negative
effect on cell surface expression of the mature wild-type receptor. Notably, the