CLONING OF THE SEROTONIN 5-HT1P RECEPTOR

THE SEROTONIN 5-HT1P RECEPTOR HAS BEEN EXTENSIVELY CHARACTERIZED IN THE ENTERIC NERVOUS SYSTEM WHERE IT FUNCTIONS IN THE REGULATION OF GASTROINTESTINAL MOTILITY. IN ADDITION, 5-HT1P-LIKE BINDING SITES HAVE BEEN DISCOVERED IN THE PERICARDIUM AND ENDOCARDIUM OF THE HEART, THE INNERVATION OF THE SKIN, AND ON PORTIONS OF THE CEREBRAL VASCULATURE WHERE THESE RECEPTORS MIGHT PLAY A ROLE IN MIGRAINE. THESE SITES HAVE NOT BEEN WIDELY STUDIED DUE TO THE DIFFICULTY IN DISSECTING THE RELATIVELY SMALL QUANTITIES OF NEURAL TISSUE FROM THE NON-NEURAL TISSUE. MOLECULAR CLONING AND HETEROLOGOUS EXPRESSION OF THE 5-HT1P RECEPTOR WILL GREATLY FACILITATE STUDY OF THIS RECEPTOR AND WILL PROVIDE A KEY TOOL FOR THE DISCOVERY OF DRUGS AFFECTING THIS RECEPTOR SITE. BOTH ELECTROPHYSIOLOGICAL AND RECEPTOR-BINDING DATA INDICATE THATTHE 5-HT1P RECEPTOR IS A MEMBER OF THE G PROTEIN RECEPTOR SUPERFAMILY. HOWEVER, THE SECOND MESSENGER TO WHICH THIS RECEPTOR IS COUPLED HAS NEVER BEEN DETERMINED. ELUCIDATION OF THE SECOND-MESSENGER PATHWAY IN PHASE I OF THIS PROJECT WILL ALLOW THE ASSIGNMENT OF THE 5-HT1P RECEPTOR TO A PARTICULAR STRUCTURAL CLASS OF SEROTONIN RECEPTORS AND WILL GREATLY FACILITATE DESIGN OF A CLONING STRATEGY. IN PHASE II, A CLONING STRATEGY WILL BE IMPLEMENTED AND THE CLONED RECEPTOR TRANSFECTED INTO MAMMALIAN CELL LINES FOR USE AS A HIGH-THROUGHPUT DRUG DISCOVERY SYSTEM.