Project Summary

Jonathan Javitch, M.D., Ph.D. (Independent Investigator 2003) of Columbia University, has recently discovered where the subunits of a G protein-coupled receptor—the D2 dopamine receptor—join and communicate. About half of all drugs on the market target a member of the 1,000 (approximate) receptors in the G protein-coupled receptor family. Until recently, it was thought that G protein-coupled receptors were solitary proteins in the cell membrane, but recent evidence now indicates that most receptors pair up with each other to form dimers (a compound formed by the union of two molecules of a simpler compound). It has been unclear whether the dimer subunits acted independently or needed each other to work. The D2 dopamine receptor is targeted by drugs that treat schizophrenia, and it is composed of 7 helices that span the membrane (it’s thought the transmembrane segments of the receptor form a bundle around a central binding pocket for dopamine). Dr. Javitch found that some parts of the receptor that affect binding aren’t in the binding pocket but are instead on the edge of the receptor in the fourth transmembrane segment (TM4), and he then speculated that the TM4 region joins two D2 receptors together in a dimer, and explored this using a technique called cysteine cross-linking. It appears that binding of ligands changes the shape of the TM4 and the shape change passes information from one dimer subunit to the other. He will now screen a library of several thousand drug-like compounds for molecules that can drive receptors apart, to determine the physiological consequences of such an action and whether such a compound may represent a new approach to the development of novel antipsychotic drugs.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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