The present invention provides cells and methods related to signaling receptors. The cells of the invention express the signaling receptors (e.g., in a constitutively active state). The cells are useful for analyzing the signaling receptors and their related pathways. The invention further provides methods for studying interactions of the signaling receptors and for small molecule screening, including high throughput methods. The invention further relates to expressing a signaling receptor (e.g., a GPCR) in a constitutively active state, even in the absence of the receptor's ligand. This allows for screening for inhibitors of the activated receptor's pathway without even knowing the ligand that activates the receptor, e.g., an orphan receptor. The invention further provides cell lines for expressing a signaling receptor in a constitutively active state. These cell lines are useful for high throughput screening assays of the invention.