Understanding RAMPs through genetically engineered mouse models.

The family of Receptor Activity Modifying Proteins (RAMPs) consists of three members, RAMP1, 2 and 3, which are each encoded by a separate gene and have diverse spatiotemporal expression patterns. Biochemical and pharmacological studies in cultured cells have shown that RAMPs can modulate several aspects of G receptor (GPCR) signaling, including receptor trafficking, ligand binding affinity, second messenger signaling and receptor desensitization. Moreover, these studies have shown that RAMPs can interact with several GPCRs other than the canonical calcitonin receptor-like receptor (CLR), with which they were first identified. Given these expanding roles for RAMPs, it becomes interesting to question how these biochemical and pharmacological properties bear significance in normal or disease physiology. To this end, several gene targeted knockout and transgenic models have been generated and characterized in recent years. Fortunately, they have each supported important roles for RAMPs during embryonic development and adulthood. This chapter provides a comprehensive overview of the most recent findings from gene targeted knockout mouse models and transgenic over-expression models, and gives special consideration to how comparative phenotyping approaches and conditional deletion strategies can be highly beneficial. In the future, these genetically engineered mouse models will provide both insights and tools for the exploitation of RAMP-based therapies for the treatment of human diseases.