Physiological rescue by functional complementation of mutated LH receptors in transgenic mice
Adolfo Rivero-Müller1, Yen-Yin Chou1,3, Svetlana Lajic2, Aylin Hanyaloglu2, Kim Jonas2, Nafis Rahman1, Tae Ji4 & Ilpo Huhtaniemi2
The LH receptor (LHR) is a 7-transmembrane domain G-protein coupled receptor (GPCR) mainly expressed in the gonads with a major role in the development and maintenance of gonadal steroidogenesis and gametogenesis. Its ligand LH, secreted by the pituitary gland, binds to the extracellular domain of LHR triggering a conformational change in the transmembrane domain and leading to activation of intracellular signalling cascades.
As a member of the GPCR family, LHR activates G-proteins as the principal means of signalling. How GPCRs generate the specific cascades of intracellular responses and gene-specific transcription is not yet fully understood. One important aspect of GPCR function is that they form dimeric and oligomeric complexes during their biosynthesis, activation, inactivation and internalisation. However, evidence for the functional importance of these receptor complexes has so far been obtained exclusively from functional in vitro and crystallography data. The proof for functional significance of GPCR interactions and cooperation in the physiological context in vivo is still missing.
Using the LHR as a model GPCR, we studied whether receptorreceptor interaction can result in full physiological response. The LHR null (LuRKO) phenotype of male mice with low testosterone production, infertility and underdeveloped gonads and genitals was completely rescued in double-transgenic (BAC) mice expressing both a binding- and a signalling-deficient mutants of LHR in the LuRKO background. The rescue normalised LH-dependent gene expression, sex steroid production, full testicular and gonadal development, as well as fertility. These results provide compelling in vivo evidence for the physiological relevance of di/oligomeric functional complementation in GPCR activation.