Use of defined-function mutants to access receptor-receptor interactions

This article describes a novel method to access functional interactions of two defective mutant receptors. As a model, luteinizing hormone receptor, a G-protein-coupled receptor, was used by coexpressing two different mutants, one defective in hormone binding and the other defective in signal generation. When these two mutants were coexpressed in a cell, the cell responded to the hormone and induced the hormone action, indicating the interaction of the two receptors and rescue of the activity. The luteinizing hormone receptor consists of a 350-amino-acid extracellular N-terminal domain (exodomain), followed by seven transmembrane domains and connecting loops (endodomain). Hormone binds to the exodomain, whereas hormone signals are generated in the endodomain. Here, we show that binding of hormone to one receptor can activate adenylyl cyclase through its transmembrane bundle, intramolecular activation (cis-activation), as well as intermolecular activation (trans-activation) through the transmembrane bundle of an adjacent receptor, without forming a stable receptor dimer. Our observations provide new insights into the mechanism of receptor activation mechanisms, and have implications for the treatment of inherited disorders of glycoprotein hormone receptors.