Selective modulation of wild type receptor functions by mutants of G-protein-coupled receptors

Members of the G-protein-coupled receptor (GPCR) family are involved in mos t aspects of higher eukaryote biology, and mutations in their coding sequen ce have been linked to several diseases. In the present study, we report th at mutant GPCR can affect the functional properties of the co-expressed wil d type (WT) receptor. Mutants of the human platelet-activating factor recep tor that fail to show any detectable ligand binding (N285I and K298stop) or coupling to a G-protein (D63N, D289A, and Y293A) were co-expressed with th e WT receptor in Chinese hamster ovary and COS-7 cells. In this context, N2 85I and K298stop mutant receptors inhibited H-3-WEB2086 binding and surface expression. Co-transfection with D63N resulted in a constitutively active receptor phenotype. Platelet-activating factor-induced inositol phosphate p roduction in cells transfected with a 1:1 ratio of WT:D63N was higher than with the WT cDNA alone but was abolished with a 1:3 ratio. We confirmed tha t these findings could be extended to other GPCRs by showing that co-expres sion of the WT C-C chemokine receptor 2b with a carboxyl-terminal deletion mutant (K311stop), resulted in a decreased affinity and responsiveness to M CP-1. A better understanding of this phenomenon could lead to important too ls for the prevention or treatment of certain diseases.