The subject invention provides methods for making ligand upregulatable G-protein coupled receptors (GPCRs). Ligand upregulatable GPCRs contain a modified TM5-IC3-TM6 segment, which provides for increased levels of the ligand upregulatable GPCR in a host cell in the presence of a ligand as compared to the absence of the ligand. The subject invention also provides assays for screening test compounds for a ligand of a GPCR using a ligand upregulatable GPCR. In these assays, a ligand upregulatable GPCR is contacted with a test compound, and an increase in the detectable amount of the ligand upregulatable GPCR in the host cell indicates that the test compound is a ligand of the GPCR. Said indicated ligands encompass modulators of the GPCR. Said modulators of the GPCR are particularly useful in treating GPCR-related conditions.